Sample records for potency database cpdb
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Gold, Lois Swirsky; Manley, Neela B.; Slone, Thomas H.
2005-04-08
The Carcinogenic Potency Database (CPDB) is a systematic and unifying resource that standardizes the results of chronic, long-term animal cancer tests which have been conducted since the 1950s. The analyses include sufficient information on each experiment to permit research into many areas of carcinogenesis. Both qualitative and quantitative information is reported on positive and negative experiments that meet a set of inclusion criteria. A measure of carcinogenic potency, TD50 (daily dose rate in mg/kg body weight/day to induce tumors in half of test animals that would have remained tumor-free at zero dose), is estimated for each tissue-tumor combination reported. Thismore » article is the ninth publication of a chronological plot of the CPDB; it presents results on 560 experiments of 188 chemicals in mice, rats, and hamsters from 185 publications in the general literature updated through 1997, and from 15 Reports of the National Toxicology Program in 1997-1998. The test agents cover a wide variety of uses and chemical classes. The CPDB Web Site(http://potency.berkeley.edu/) presents the combined database of all published plots in a variety of formats as well as summary tables by chemical and by target organ, supplemental materials on dosing and survival, a detailed guide to using the plot formats, and documentation of methods and publications. The overall CPDB, including the results in this article, presents easily accessible results of 6153 experiments on 1485 chemicals from 1426 papers and 429 NCI/NTP (National Cancer Institute/National Toxicology program) Technical Reports. A tab-separated format of the full CPDB for reading the data into spreadsheets or database applications is available on the Web Site.« less
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Gold, L S; Manley, N B; Slone, T H; Garfinkel, G B; Ames, B N; Rohrbach, L; Stern, B R; Chow, K
1995-01-01
This paper presents two types of information from the Carcinogenic Potency Database (CPDB): (a) the sixth chronological plot of analyses of long-term carcinogenesis bioassays, and (b) an index to chemicals in all six plots, including a summary compendium of positivity and potency for each chemical (Appendix 14). The five earlier plots of the CPDB have appeared in this journal, beginning in 1984 (1-5). Including the plot in this paper, the CPDB reports results of 5002 experiments on 1230 chemicals. This paper includes bioassay results published in the general literature between January 1989 and December 1990, and in Technical Reports of the National Toxicology Program between January 1990 and June 1993. Analyses are included on 17 chemicals tested in nonhuman primates by the Laboratory of Chemical Pharmacology, National Cancer Institute. This plot presents results of 531 long-term, chronic experiments of 182 test compounds and includes the same information about each experiment in the same plot format as the earlier papers: the species and strain of test animal, the route and duration of compound administration, dose level and other aspects of experimental protocol, histopathology and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, author's opinion about carcinogenicity, and literature citation. We refer the reader to the 1984 publications (1,6,7) for a detailed guide to the plot of the database, a complete description of the numerical index of carcinogenic potency, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The six plots of the CPDB are to be used together since results of individual experiments that were published earlier are not repeated. Appendix 14 is designed to facilitate access to results on all chemicals. References to the published papers that are the source of experimental data are reported in each of the published plots. For readers using the CPDB extensively, a combined plot is available of all results from the six separate plot papers, ordered alphabetically by chemical; the combined plot in printed form or on computer tape or diskette is available from the first author. A SAS database is also available. PMID:8741772
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Gold, L S; Manley, N B; Slone, T H; Rohrbach, L
1999-01-01
The Carcinogenic Potency Database (CPDB) is a systematic and unifying analysis of results of chronic, long-term cancer tests. This paper presents a supplemental plot of the CPDB, including 513 experiments on 157 test compounds published in the general literature in 1993 and 1994 and in Technical Reports of the National Toxicology Program in 1995 and 1996. The plot standardizes the experimental results (whether positive or negative for carcinogenicity), including qualitative data on strain, sex, route of compound administration, target organ, histopathology, and author's opinion and reference to the published paper, as well as quantitative data on carcinogenic potency, statistical significance, tumor incidence, dose-response curve shape, length of experiment, duration of dosing, and dose rate. A numerical description of carcinogenic potency, the TD(subscript)50(/subscript), is estimated for each set of tumor incidence data reported. When added to the data published earlier, the CPDB now includes results of 5,620 experiments on 1,372 chemicals that have been reported in 1,250 published papers and 414 National Cancer Institute/National Toxicology Program Technical Reports. The plot presented here includes detailed analyses of 25 chemicals tested in monkeys for up to 32 years by the National Cancer Institute. Half the rodent carcinogens that were tested in monkeys were not carcinogenic, despite usually strong evidence of carcinogenicity in rodents and/or humans. Our analysis of possible explanatory factors indicates that this result is due in part to the fact that the monkey studies lacked power to detect an effect compared to standard rodent bioassays. Factors that contributed to the lack of power are the small number of animals on test; a stop-exposure protocol for model rodent carcinogens; in a few cases, toxic doses that resulted in stoppage of dosing or termination of the experiment; and in a few cases, low doses administered to monkeys or early termination of the experiment even though the doses were not toxic. Among chemicals carcinogenic in both monkeys and rodents, there is some support for target site concordance, but it is primarily restricted to liver tumors. Potency values are highly correlated between rodents and monkeys. The plot in this paper can be used in conjunction with the earlier results published in the CRC Handbook of Carcinogenic Potency and Genotoxicity Databases [Gold LS, Zeiger E, eds. Boca Raton FL:CRC Press, 1997] and with our web site (http://potency.berkeley.edu), which includes a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency (TD50), and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Two summary tables permit easy access to the literature of animal cancer tests by target organ and by chemical. For readers using the CPDB extensively, a combined plot on diskette or other format is available from the first author. It includes all results published earlier and in this paper, ordered alphabetically by chemical. A SAS database is also available. PMID:10421768
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Carcinogenicity and Mutagenicity Data: New Initiatives to ...
Currents models for prediction of chemical carcinogenicity and mutagenicity rely upon a relatively small number of publicly available data resources, where the data being modeled are highly summarized and aggregated representations of the actual experimental results. A number of new initiatives are underway to improve access to existing public carcinogenicity and mutagenicity data for use in modeling, as well as to encourage new approaches to the use of data in modeling. Rodent bioassay results from the NIEHS National Toxicology Program (NTP) and the Berkeley Carcinogenic Potency Database (CPDB) have provided the largest public data resources for building carcinogenicity prediction models to date. However, relatively few and limited representations of these data have actually informed existing models. Initiatives, such as EPA's DSSTox Database Network, offer elaborated and quality reviewed presentations of the CPDB and expanded data linkages and coverage of chemical space for carcinogenicity and mutagenicity. In particular the latest published DSSTox CPDBAS structure-data file includes a number of species-specific and summary activity fields, including a species-specific normalized score for carcinogenic potency (TD50) and various weighted summary activities. These data are being incorporated into PubChem to provide broad
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Gold, L S; Manley, N B; Slone, T H; Garfinkel, G B; Rohrbach, L; Ames, B N
1993-01-01
This paper is the fifth plot of the Carcinogenic Potency Database (CPDB) that first appeared in this journal in 1984 (1-5). We report here results of carcinogenesis bioassays published in the general literature between January 1987 and December 1988, and in technical reports of the National Toxicology Program between July 1987 and December 1989. This supplement includes results of 412 long-term, chronic experiments of 147 test compounds and reports the same information about each experiment in the same plot format as the earlier papers: the species and strain of test animal, the route and duration of compound administration, dose level and other aspects of experimental protocol, histopathology and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, author's opinion about carcinogenicity, and literature citation. We refer the reader to the 1984 publications (1,5,6) for a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The five plots of the database are to be used together, as results of individual experiments that were published earlier are not repeated. In all, the five plots include results of 4487 experiments on 1136 chemicals. Several analyses based on the CPDB that were published earlier are described briefly, and updated results based on all five plots are given for the following earlier analyses: the most potent TD50 value by species, reproducibility of bioassay results, positivity rates, and prediction between species.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8354183
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Target organs in chronic bioassays of 533 chemical carcinogens
DOE Office of Scientific and Technical Information (OSTI.GOV)
Gold, L.S.; Slone, T.H.; Manley, N.B.
1991-06-01
A compendium of carcinogenesis bioassay results organized by target organ is presented for 533 chemicals that are carcinogenic in at least one species. This compendium is based primarily on experiments in rats or mice; results in hamsters, nonhuman primates, and dogs are also reported. The compendium can be used to identify chemicals that induce tumors at particular sites, and to determine whether target sites are the same for chemicals positive in more than one species. The Carcinogenic Potency Database (CPDB), which includes results of 3969 experiments, is used in the analysis. The published CPDB includes details on each test, andmore » literature references. Chemical carcinogens are reported for 35 different target organs in rats or mice. More than 80% of the carcinogens in each of these species are positive in at least one of the 8 most frequent target sites; liver, lung, mammary gland, stomach, vascular system, kidney, hematopoietic system, and urinary bladder. An analysis is presented of how well one can predict the carcinogenic response in mice from results in rats, or vice versa. Among chemicals tested in both species, 76% of rat carcinogens are positive in mice, and 71% of mouse carcinogens are positive in rats. Prediction is less accurate to the same target site: 52% of rat carcinogens are positive in the same site in mice, and 48% of mouse carcinogens are positive in the same site in rats. The liver is the most frequent site in common between rats and mice.« less
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Chen, Lei; Chu, Chen; Lu, Jing; Kong, Xiangyin; Huang, Tao; Cai, Yu-Dong
2015-09-01
Cancer is one of the leading causes of human death. Based on current knowledge, one of the causes of cancer is exposure to toxic chemical compounds, including radioactive compounds, dioxin, and arsenic. The identification of new carcinogenic chemicals may warn us of potential danger and help to identify new ways to prevent cancer. In this study, a computational method was proposed to identify potential carcinogenic chemicals, as well as non-carcinogenic chemicals. According to the current validated carcinogenic and non-carcinogenic chemicals from the CPDB (Carcinogenic Potency Database), the candidate chemicals were searched in a weighted chemical network constructed according to chemical-chemical interactions. Then, the obtained candidate chemicals were further selected by a randomization test and information on chemical interactions and structures. The analyses identified several candidate carcinogenic chemicals, while those candidates identified as non-carcinogenic were supported by a literature search. In addition, several candidate carcinogenic/non-carcinogenic chemicals exhibit structural dissimilarity with validated carcinogenic/non-carcinogenic chemicals.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Singh, Kunwar P., E-mail: kpsingh_52@yahoo.com; Environmental Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box 80, Mahatma Gandhi Marg, Lucknow 226 001; Gupta, Shikha
Robust global models capable of discriminating positive and non-positive carcinogens; and predicting carcinogenic potency of chemicals in rodents were developed. The dataset of 834 structurally diverse chemicals extracted from Carcinogenic Potency Database (CPDB) was used which contained 466 positive and 368 non-positive carcinogens. Twelve non-quantum mechanical molecular descriptors were derived. Structural diversity of the chemicals and nonlinearity in the data were evaluated using Tanimoto similarity index and Brock–Dechert–Scheinkman statistics. Probabilistic neural network (PNN) and generalized regression neural network (GRNN) models were constructed for classification and function optimization problems using the carcinogenicity end point in rat. Validation of the models wasmore » performed using the internal and external procedures employing a wide series of statistical checks. PNN constructed using five descriptors rendered classification accuracy of 92.09% in complete rat data. The PNN model rendered classification accuracies of 91.77%, 80.70% and 92.08% in mouse, hamster and pesticide data, respectively. The GRNN constructed with nine descriptors yielded correlation coefficient of 0.896 between the measured and predicted carcinogenic potency with mean squared error (MSE) of 0.44 in complete rat data. The rat carcinogenicity model (GRNN) applied to the mouse and hamster data yielded correlation coefficient and MSE of 0.758, 0.71 and 0.760, 0.46, respectively. The results suggest for wide applicability of the inter-species models in predicting carcinogenic potency of chemicals. Both the PNN and GRNN (inter-species) models constructed here can be useful tools in predicting the carcinogenicity of new chemicals for regulatory purposes. - Graphical abstract: Figure (a) shows classification accuracies (positive and non-positive carcinogens) in rat, mouse, hamster, and pesticide data yielded by optimal PNN model. Figure (b) shows generalization and predictive abilities of the interspecies GRNN model to predict the carcinogenic potency of diverse chemicals. - Highlights: • Global robust models constructed for carcinogenicity prediction of diverse chemicals. • Tanimoto/BDS test revealed structural diversity of chemicals and nonlinearity in data. • PNN/GRNN successfully predicted carcinogenicity/carcinogenic potency of chemicals. • Developed interspecies PNN/GRNN models for carcinogenicity prediction. • Proposed models can be used as tool to predict carcinogenicity of new chemicals.« less
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Physiology and pathogenicity of cpdB deleted mutant of avian pathogenic Escherichia coli.
Liu, Huifang; Chen, Liping; Si, Wei; Wang, Chunlai; Zhu, Fangna; Li, Guangxing; Liu, Siguo
2017-04-01
Avian colibacillosis is one of the most common infectious diseases caused partially or entirely by avian pathogenic Escherichia coli (APEC) in birds. In addition to spontaneous infection, APEC can also cause secondary infections that result in greater severity of illness and greater losses to the poultry industry. In order to assess the role of 2', 3'-cyclic phosphodiesterase (cpdB) in APEC on disease physiology and pathogenicity, an avian pathogenic Escherichia coli-34 (APEC-34) cpdB mutant was obtained using the Red system. The cpdB mutant grew at a slower rate than the natural strain APEC-34. Scanning electron microscopy (SEM) indicated that the bacteria of the cpdB mutant were significantly longer than the bacteria observed in the natural strain (P<0.01), and that the width of the cpdB mutant was significantly smaller than its natural counterpart (P<0.01). In order to evaluate the role of cpdB in APEC in the colonization of internal organs (lung, liver and spleen) in poultry, seven-day-old SPF chicks were infected with 10 9 CFU/chick of the cpdB mutant or the natural strain. No colonizations of cpdB mutants were observed in the internal organs 10days following the infection, though numerous natural strains were observed at 20days following infection. Additionally, the relative expression of division protein ftsZ, outer membrane protein A ompA, ferric uptake regulator fur and tryptophanase tnaA genes in the mutant strain were all significantly lower than in the natural strain (P<0.05 or P<0.01). These results suggested that cpdB is involved in the long-term colonization of APEC in the internal organs of the test subjects. The deletion of the cpdB gene also significantly affected the APEC growth and morphology. Copyright © 2016. Published by Elsevier Ltd.
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Cupriavidus pampae sp. nov., a novel herbicide-degrading bacterium isolated from agricultural soil.
Cuadrado, Virginia; Gomila, Margarita; Merini, Luciano; Giulietti, Ana M; Moore, Edward R B
2010-11-01
A bacterial consortium able to degrade the herbicide 4-(2,4-dichlorophenoxy) butyric acid (2,4-DB) was obtained from an agricultural soil of the Argentinean Humid Pampa region which has a history of long-term herbicide use. Four bacterial strains were isolated from the consortium and identified as members of the genera Cupriavidus, Labrys and Pseudomonas. A polyphasic systematic analysis was carried out on strain CPDB6(T), the member of the 2,4-DB-degrading consortium able to degrade 2,4-DB as a sole carbon and energy source. The Gram-negative, rod-shaped, motile, non-sporulating, non-fermenting bacterium was shown to belong to the genus Cupriavidus on the basis of 16S rRNA gene sequence analyses. Strain CPDB6(T) did not reduce nitrate, which differentiated it from the type species of the genus, Cupriavidus necator; it did not grow in 0.5-4.5 % NaCl, although most species of Cupriavidus are able to grow at NaCl concentrations as high as 1.5 %; and it was able to deamidate acetamide, which differentiated it from all other species of Cupriavidus. DNA-DNA hybridization data revealed low levels of genomic DNA similarity (less than 30 %) between strain CPDB6(T) and the type strains of Cupriavidus species with validly published names. The major cellular fatty acids detected were cis-9-hexadecenoic (16 : 1ω7c) and hexadecanoic (16 : 0) acids. On the basis of phenotypic and genotypic characterizations, strain CPDB6(T) was recognized as a representative of a novel species within the genus Cupriavidus. The name Cupriavidus pampae sp. nov. is proposed, with strain CPDB6(T) (=CCUG 55948(T)=CCM-A-29:1289(T)) as the type strain.
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Submarine seep of carbon dioxide in Norton Sound, Alaska
Kvenvolden, K.A.; Weliky, K.; Nelson, H.; Des Marais, D.J.
1979-01-01
Earlier workers have described a submarine gas seep in Norton Sound having an unusual mixture of petroleum-like, low-molecular-weight hydrocarbons. Actually, only about 0.04 percent of the seeping gas is hydrocarbons and 98 percent is carbon dioxide. The isotopic compositions of carbon dioxide (??13CPDB = -2.7 per mil) and methane (??13CPDB = -36 per mil, where PDB is the Peedee belemnite standard) indicate that geothermal processes are active here. Copyright ?? 1979 AAAS.
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Toxico-Cheminformatics and QSPR Modeling of the Carcinogenic Potency Database
Report on the development of a tiered, confirmatory scheme for prediction of chemical carcinogenicity based on QSAR studies of compounds with available mutagenic and carcinogenic data. For 693 such compounds from the Carcinogenic Potency Database characterized molecular topologic...
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A carcinogenic potency database of the standardized results of animal bioassays
Gold, Lois Swirsky; Sawyer, Charles B.; Magaw, Renae; Backman, Georganne M.; De Veciana, Margarita; Levinson, Robert; Hooper, N. Kim; Havender, William R.; Bernstein, Leslie; Peto, Richard; Pike, Malcolm C.; Ames, Bruce N.
1984-01-01
The preceding paper described our numerical index of carcinogenic potency, the TD50 and the statistical procedures adopted for estimating it from experimental data. This paper presents the Carcinogenic Potency Database, which includes results of about 3000 long-term, chronic experiments of 770 test compounds. Part II is a discussion of the sources of our data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Part III is a guide to the plot of results presented in Part IV. A number of appendices are provided to facilitate use of the database. The plot includes information about chronic cancer tests in mammals, such as dose and other aspects of experimental protocol, histopathology and tumor incidence, TD50 and its statistical significance, dose response, author's opinion and literature reference. The plot readily permits comparisons of carcinogenic potency and many other aspects of cancer tests; it also provides quantitative information about negative tests. The range of carcinogenic potency is over 10 million-fold. PMID:6525996
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Song, Min-Ae; Marian, Catalin; Brasky, Theodore M; Reisinger, Sarah; Djordjevic, Mirjana; Shields, Peter G
2016-03-14
Use of smokeless tobacco products (STPs) is associated with oral cavity cancer and other health risks. Comprehensive analysis for chemical composition and toxicity is needed to compare conventional and newer STPs with lower tobacco-specific nitrosamines (TSNAs) yields. Seven conventional and 12 low-TSNA moist snuff products purchased in the U.S., Sweden, and South Africa were analyzed for 18 chemical constituents (International Agency for Research on Cancer classified carcinogens), pH, nicotine, and free nicotine. Chemicals were compared in each product using Wilcoxon rank-sum test and principle component analysis (PCA). Conventional compared to low-TSNA moist snuff products had higher ammonia, benzo[a]pyrene, cadmium, nickel, nicotine, nitrate, and TSNAs and had lower arsenic in dry weight content and per mg nicotine. Lead and chromium were significantly higher in low-TSNA moist snuff products. PCA showed a clear difference for constituents between conventional and low-TSNA moist snuff products. Differences among products were reduced when considered on a per mg nicotine basis. As one way to contextualize differences in constituent levels, probabilistic lifetime cancer risk was estimated for chemicals included in The University of California's carcinogenic potency database (CPDB). Estimated probabilistic cancer risks were 3.77-fold or 3-fold higher in conventional compared to low-TSNA moist snuff products under dry weight or under per mg nicotine content, respectively. In vitro testing for the STPs indicated low level toxicity and no substantial differences. The comprehensive chemical characterization of both conventional and low-TSNA moist snuff products from this study provides a broader assessment of understanding differences in carcinogenic potential of the products. In addition, the high levels and probabilistic cancer risk estimates for certain chemical constituents of smokeless tobacco products will further inform regulatory decision makers and aid them in their efforts to reduce carcinogen exposure in smokeless tobacco products. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
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Carbon and its isotopes in mid-oceanic basaltic glasses
Des Marais, D.J.; Moore, J.G.
1984-01-01
Three carbon components are evident in eleven analyzed mid-oceanic basalts: carbon on sample surfaces (resembling adsorbed gases, organic matter, or other non-magmatic carbon species acquired by the glasses subsequent to their eruption), mantle carbon dioxide in vesicles, and mantle carbon dissolved in the glasses. The combustion technique employed recovered only reduced sulfur, all of which appears to be indigenous to the glasses. The dissolved carbon concentration (measured in vesicle-free glass) increases with the eruption depth of the spreading ridge, and is consistent with earlier data which show that magma carbon solubility increases with pressure. The total glass carbon content (dissolved plus vesicular carbon) may be controlled by the depth of the shallowest ridge magma chamber. Carbon isotopic fractionation accompanies magma degassing; vesicle CO2 is about 3.8??? enriched in 13C, relative to dissolved carbon. Despite this fractionation, ??13CPDB values for all spreading ridge glasses lie within the range -5.6 and -7.5, and the ??13CPDB of mantle carbon likely lies between -5 and -7. The carbon abundances and ??13CPDB values of Kilauea East Rift glasses apparently are influenced by the differentiation and movement of magma within that Hawaiian volcano. Using 3He and carbon data for submarine hydrothermal fluids, the present-day mid-oceanic ridge mantle carbon flux is estimated very roughly to be about 1.0 ?? 1013 g C/yr. Such a flux requires 8 Gyr to accumulate the earth's present crustal carbon inventory. ?? 1984.
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Gold, L S; Slone, T H; Backman, G M; Magaw, R; Da Costa, M; Lopipero, P; Blumenthal, M; Ames, B N
1987-01-01
This paper is the second chronological supplement to the Carcinogenic Potency Database, published earlier in this journal (1,2,4). We report here results of carcinogenesis bioassays published in the general literature between January 1983 and December 1984, and in Technical Reports of the National Cancer Institute/National Toxicology Program between January 1983 and May 1986. This supplement includes results of 525 long-term, chronic experiments of 199 test compounds, and reports the same information about each experiment in the same plot format as the earlier papers: e.g., the species and strain of test animal, the route and duration of compound administration, dose level and other aspects of experimental protocol, histopathology and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, author's opinion about carcinogenicity, and literature citation. We refer the reader to the 1984 publications for a description of the numerical index of carcinogenic potency (TD50), a guide to the plot of the database, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The three plots of the database are to be used together, since results of experiments published in earlier plots are not repeated. Taken together, the three plots include results for more than 3500 experiments on 975 chemicals. Appendix 14 is an index to all chemicals in the database and indicates which plot(s) each chemical appears in. PMID:3691431
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Faure, G.; Botoman, G.
1984-01-01
Isotopic compositions of oxygen, carbon and strontium of calcite cleats in coal seams of southern Victoria Land, Antarctica, and Tuscarawas County, Ohio, contain a record of the conditions a the time of their formation. The Antarctic calcites (?? 18O(SMOW) = +9.14 to +11.82%0) were deposited from waters enriched in 16O whose isotopic composition was consistent with that of meteoric precipitation at low temperature and high latitude. The carbon of the calcite cleats (?? 13C(PDB) = -15.6 to -16.9%0) was derived in part from the coal (?? 13C(PDB) = -23.5 to -26.7%0) as carbon dioxide and by oxidation of methane or other hydrocarbon gases. The strontium ( 87Sr 86Sr = 0.71318-0.72392) originated primarily from altered feldspar grains in the sandstones of the Beacon Supergroup. Calcite cleats in the Kittaning No. 6 coal seam of Ohio (?? 18O(SMOW) = +26.04 to +27.79%0) were deposited from waters that had previously exchanged oxygen, possibly with marine carbonate at depth. The carbon (?? 13C(PDB) = 0.9 to +2.4%0) is enriched in 13C even though that cleats were deposited in coal that is highly enriched in 12C and apparently originated from marine carbonates. Strontium in the cleats ( Sr 87 0.71182-0.71260) is not of marine origin but contains varying amounts of radiogenic 87Sr presumably derived from detrital Rb-bearing minerals in the adjacent sedimentary rocks. The results of this study suggest that calcite cleats in coal of southern Victoria Land, Antarctica, were deposited after the start of glaciation in Cenozoic time and that those in Ohio precipitated from formation waters derived from the underlying marine carbonate rocks, probably in the recent geologic past. ?? 1984.
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Gold, L S; Slone, T H; Backman, G M; Eisenberg, S; Da Costa, M; Wong, M; Manley, N B; Rohrbach, L; Ames, B N
1990-01-01
This paper is the third chronological supplement to the Carcinogenic Potency Database that first appeared in this journal in 1984. We report here results of carcinogenesis bioassays published in the general literature between January 1985 and December 1986, and in Technical Reports of the National Toxicology Program between June 1986 and June 1987. This supplement includes results of 337 long-term, chronic experiments of 121 compounds, and reports the same information about each experiment in the same plot format as the earlier papers, e.g., the species and strain of animal, the route and duration of compound administration, dose level, and other aspects of experimental protocol, histopathology, and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, opinion of the author about carcinogenicity, and literature citation. The reader needs to refer to the 1984 publication for a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The four plots of the database are to be used together as results published earlier are not repeated. In all, the four plots include results for approximately 4000 experiments on 1050 chemicals. Appendix 14 of this paper is an alphabetical index to all chemicals in the database and indicates which plot(s) each chemical appears in. A combined plot of all results from the four separate papers, that is ordered alphabetically by chemical, is available from the first author, in printed form or on computer tape or diskette. PMID:2351123
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Advances in Toxico-Cheminformatics: Supporting a New ...
EPA’s National Center for Computational Toxicology is building capabilities to support a new paradigm for toxicity screening and prediction through the harnessing of legacy toxicity data, creation of data linkages, and generation of new high-throughput screening (HTS) data. The DSSTox project is working to improve public access to quality structure-annotated chemical toxicity information in less summarized forms than traditionally employed in SAR modeling, and in ways that facilitate both data-mining and read-across. Both DSSTox Structure-Files and the dedicated on-line DSSTox Structure-Browser are enabling seamless structure-based searching and linkages to and from previously isolated, chemically indexed public toxicity data resources (e.g., NTP, EPA IRIS, CPDB). Most recently, structure-enabled search capabilities have been extended to chemical exposure-related microarray experiments in the public EBI Array Express database, additionally linking this resource to the NIEHS CEBS toxicogenomics database. The public DSSTox chemical and bioassay inventory has been recently integrated into PubChem, allowing a user to take full advantage of PubChem structure-activity and bioassay clustering features. The DSSTox project is providing cheminformatics support for EPA’s ToxCastTM project, as well as supporting collaborations with the National Toxicology Program (NTP) HTS and the NIH Chemical Genomics Center (NCGC). Phase I of the ToxCastTM project is generating HT
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Carbon isotopic composition of individual Precambrian microfossils
NASA Technical Reports Server (NTRS)
House, C. H.; Schopf, J. W.; McKeegan, K. D.; Coath, C. D.; Harrison, T. M.; Stetter, K. O.
2000-01-01
Ion microprobe measurements of carbon isotope ratios were made in 30 specimens representing six fossil genera of microorganisms petrified in stromatolitic chert from the approximately 850 Ma Bitter Springs Formation, Australia, and the approximately 2100 Ma Gunflint Formation, Canada. The delta 13C(PDB) values from individual microfossils of the Bitter Springs Formation ranged from -21.3 +/- 1.7% to -31.9 +/- 1.2% and the delta 13C(PDB) values from microfossils of the Gunflint Formation ranged from -32.4 +/- 0.7% to -45.4 +/- 1.2%. With the exception of two highly 13C-depleted Gunflint microfossils, the results generally yield values consistent with carbon fixation via either the Calvin cycle or the acetyl-CoA pathway. However, the isotopic results are not consistent with the degree of fractionation expected from either the 3-hydroxypropionate cycle or the reductive tricarboxylic acid cycle, suggesting that the microfossils studied did not use either of these pathways for carbon fixation. The morphologies of the microfossils suggest an affinity to the cyanobacteria, and our carbon isotopic data are consistent with this assignment.
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Woo, Seung Hyo; Kang, Dong Il; Ha, Yun-Sok; Salmasi, Amirali Hassanzadeh; Kim, Jeong Hyun; Lee, Dong-Hyeon; Kim, Wun-Jae; Kim, Isaac Yi
2014-02-01
The recovery of potency following radical prostatectomy is complex and has a very wide range. In this study, we analyzed in detail the precise pattern of recovery of potency following robot-assisted radical prostatectomy (RARP). Prospectively collected database of patients with a minimum follow-up of 1 year after RARP were evaluated retrospectively. Of 503 patients identified, 483 patients completed the sexual health inventory for men (SHIM) preoperatively and postoperatively every 3 months for the first 12 months. Overall potency, usage of phosphodiesterase type-5 (PDE-5) inhibitors, and return to baseline erectile function were evaluated. Potency was defined as having erection that is sufficient for sexual intercourse more than 50% of attempts, while quality potency was defined as being potent without the use of PDE-5 inhibitors. Preoperatively, the overall potency and quality potency rate were 67.1% and 48.1%, respectively. Postoperatively, the overall potency rate was 61.4%, while the quality potency rate was 37.2%. In multivariate regression analysis, independent predictors of potency recovery were young age (<60), preoperative potency status, and bilateral preservation of neurovascular bundles (NVBs). In men with SHIM>21, the overall potency and quality potency rate were 79.7% and 41.2%, respectively. More importantly, only 21.4% of the men with normal erection preoperatively (SHIM>21) returned to baseline erectile function (SHIM>21) 12 months after surgery. This study indicates that young age (<60), preoperative potency, and bilateral preservation of NVBs were positive predictors of potency recovery following RARP. However, an overwhelming majority of men experience a deterioration in the overall quality of erection after RARP.
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Integrated web visualizations for protein-protein interaction databases.
Jeanquartier, Fleur; Jean-Quartier, Claire; Holzinger, Andreas
2015-06-16
Understanding living systems is crucial for curing diseases. To achieve this task we have to understand biological networks based on protein-protein interactions. Bioinformatics has come up with a great amount of databases and tools that support analysts in exploring protein-protein interactions on an integrated level for knowledge discovery. They provide predictions and correlations, indicate possibilities for future experimental research and fill the gaps to complete the picture of biochemical processes. There are numerous and huge databases of protein-protein interactions used to gain insights into answering some of the many questions of systems biology. Many computational resources integrate interaction data with additional information on molecular background. However, the vast number of diverse Bioinformatics resources poses an obstacle to the goal of understanding. We present a survey of databases that enable the visual analysis of protein networks. We selected M=10 out of N=53 resources supporting visualization, and we tested against the following set of criteria: interoperability, data integration, quantity of possible interactions, data visualization quality and data coverage. The study reveals differences in usability, visualization features and quality as well as the quantity of interactions. StringDB is the recommended first choice. CPDB presents a comprehensive dataset and IntAct lets the user change the network layout. A comprehensive comparison table is available via web. The supplementary table can be accessed on http://tinyurl.com/PPI-DB-Comparison-2015. Only some web resources featuring graph visualization can be successfully applied to interactive visual analysis of protein-protein interaction. Study results underline the necessity for further enhancements of visualization integration in biochemical analysis tools. Identified challenges are data comprehensiveness, confidence, interactive feature and visualization maturing.
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Ordovician reef-hosted Jiaodingshan Mn-Co deposit and Dawashan Mn deposit, Sichuan Province, China
Fan, Delian; Hein, James R.; Ye, Jie
1999-01-01
The Jiaodingshan Mn-Co and Dawashan Mn deposits are located in the approximately 2-m thick Daduhe unit of the Wufengian strata of Late Ordovician (Ashgill) age. Paleogeographic reconstruction places the deposits at the time of their formation in a gulf between Chengdu submarine rise and the Kangdian continent. The Jiaodingshan and Dawashan deposits occur in algal-reef facies, the former in an atoll-like structure and the latter in a pinnacle reef. Ores are mainly composed of rhodochrosite, kutnahorite, hausmannite, braunite, manganosite, and bementite. Dark red, yellowish-pink, brown, green-gray, and black ores are massive, banded, laminated, spheroidal, and cryptalgal (oncolite, stromatolite, algal filaments) boundstones. Blue, green, and red algal fossils show in situ growth positions. Samples of high-grade Jiaodingshan and Dawashan ores assay as much as 66.7% MnO. Jiaodingshan Mn carbonate ores have mean contents of Ba, Co, and Pb somewhat higher than in Dawashan ores. Cobalt is widely distributed and strongly enriched in all rock types as compared to its crustal mean content. Cobalt is correlated with Cu, Ni, and MgO in both deposits and additionally with Ba and Zn in the Dawashan deposit. The δ13C(PDB) values of Mn carbonate ores (-7.8 to -16.3‰) indicate contributions of carbon from both seawater bicarbonate and the bacterial degradation of organic matter, the latter being 33% to 68%, assuming about -24‰ for the δ13C(PDB) of the organic matter. Host limestones derived carbon predominantly from seawater bicarbonate δ1313C(PDB) of +0.2 to -7‰). NW-trending fault zones controlled development of lithofacies, whereas NE-trending fault zones provided pathways for movement of fluids. The source of Co, Ni, and Cu was mainly from weathering of mafic and ultramafic rocks on the Kangdian continent, whereas contemporaneous volcanic eruptions were of secondary importance. The reefs were likely mineralized during early diagenesis under shallow burial. The reefs were highly porous and acted as the locus for metasomatic replacement by Mn that combined with CO2 produced during oxidation of organic matter in the zone of sulfate reduction and seawater bicarbonate. That metasomatic replacement formed the rhodochrosite ores.
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The finite, kinematic rupture properties of great-sized earthquakes since 1990
Hayes, Gavin
2017-01-01
Here, I present a database of >160 finite fault models for all earthquakes of M 7.5 and above since 1990, created using a consistent modeling approach. The use of a common approach facilitates easier comparisons between models, and reduces uncertainties that arise when comparing models generated by different authors, data sets and modeling techniques.I use this database to verify published scaling relationships, and for the first time show a clear and intriguing relationship between maximum potency (the product of slip and area) and average potency for a given earthquake. This relationship implies that earthquakes do not reach the potential size given by the tectonic load of a fault (sometimes called “moment deficit,” calculated via a plate rate over time since the last earthquake, multiplied by geodetic fault coupling). Instead, average potency (or slip) scales with but is less than maximum potency (dictated by tectonic loading). Importantly, this relationship facilitates a more accurate assessment of maximum earthquake size for a given fault segment, and thus has implications for long-term hazard assessments. The relationship also suggests earthquake cycles may not completely reset after a large earthquake, and thus repeat rates of such events may appear shorter than is expected from tectonic loading. This in turn may help explain the phenomenon of “earthquake super-cycles” observed in some global subduction zones.
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The finite, kinematic rupture properties of great-sized earthquakes since 1990
NASA Astrophysics Data System (ADS)
Hayes, Gavin P.
2017-06-01
Here, I present a database of >160 finite fault models for all earthquakes of M 7.5 and above since 1990, created using a consistent modeling approach. The use of a common approach facilitates easier comparisons between models, and reduces uncertainties that arise when comparing models generated by different authors, data sets and modeling techniques. I use this database to verify published scaling relationships, and for the first time show a clear and intriguing relationship between maximum potency (the product of slip and area) and average potency for a given earthquake. This relationship implies that earthquakes do not reach the potential size given by the tectonic load of a fault (sometimes called ;moment deficit,; calculated via a plate rate over time since the last earthquake, multiplied by geodetic fault coupling). Instead, average potency (or slip) scales with but is less than maximum potency (dictated by tectonic loading). Importantly, this relationship facilitates a more accurate assessment of maximum earthquake size for a given fault segment, and thus has implications for long-term hazard assessments. The relationship also suggests earthquake cycles may not completely reset after a large earthquake, and thus repeat rates of such events may appear shorter than is expected from tectonic loading. This in turn may help explain the phenomenon of ;earthquake super-cycles; observed in some global subduction zones.
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McDonough, EmilyKate; Kamp, Heather
2015-01-01
Summary Phosphate is essential for life, being used in many core processes such as signal transduction and synthesis of nucleic acids. The waterborne agent of cholera, V ibrio cholerae, encounters phosphate limitation in both the aquatic environment and human intestinal tract. This bacterium can utilize extracellular DNA (eDNA) as a phosphate source, a phenotype dependent on secreted endo‐ and exonucleases. However, no transporter of nucleotides has been identified in V . cholerae, suggesting that in order for the organism to utilize the DNA as a phosphate source, it must first separate the phosphate and nucleoside groups before transporting phosphate into the cell. In this study, we investigated the factors required for assimilation of phosphate from eDNA. We identified PhoX, and the previously unknown proteins UshA and CpdB as the major phosphatases that allow phosphate acquisition from eDNA and nucleotides. We demonstrated separable but partially overlapping roles for the three phosphatases and showed that the activity of PhoX and CpdB is induced by phosphate limitation. Thus, this study provides mechanistic insight into how V . cholerae can acquire phosphate from extracellular DNA, which is likely to be an important phosphate source in the environment and during infection. PMID:26175126
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McDonough, EmilyKate; Kamp, Heather; Camilli, Andrew
2016-02-01
Phosphate is essential for life, being used in many core processes such as signal transduction and synthesis of nucleic acids. The waterborne agent of cholera, Vibrio cholerae, encounters phosphate limitation in both the aquatic environment and human intestinal tract. This bacterium can utilize extracellular DNA (eDNA) as a phosphate source, a phenotype dependent on secreted endo- and exonucleases. However, no transporter of nucleotides has been identified in V. cholerae, suggesting that in order for the organism to utilize the DNA as a phosphate source, it must first separate the phosphate and nucleoside groups before transporting phosphate into the cell. In this study, we investigated the factors required for assimilation of phosphate from eDNA. We identified PhoX, and the previously unknown proteins UshA and CpdB as the major phosphatases that allow phosphate acquisition from eDNA and nucleotides. We demonstrated separable but partially overlapping roles for the three phosphatases and showed that the activity of PhoX and CpdB is induced by phosphate limitation. Thus, this study provides mechanistic insight into how V. cholerae can acquire phosphate from extracellular DNA, which is likely to be an important phosphate source in the environment and during infection. © 2015 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.
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Mya, Khine Y; Lin, Esther M J; Gudipati, Chakravarthy S; Gose, Halima B A S; He, Chaobin
2010-07-22
Poly(hexafluorobutyl methacrylate) (PHFBMA) homopolymer was synthesized by reversible addition-fragmentation chain transfer (RAFT)-mediated living radical polymerization in the presence of cyano-2-propyl dithiobenzoate (CPDB) RAFT agent. A block copolymer of PHFBMA-poly(propylene glycol acrylate) (PHFBMA-b-PPGA) with dangling poly(propylene glycol) (PPG) side chains was then synthesized by using CPDB-terminated PHFBMA as a macro-RAFT agent. The amphiphilic properties and self-assembly of PHFBMA-b-PPGA block copolymer in aqueous solution were investigated by dynamic and static light scattering (DLS and SLS) studies, in combination with fluorescence spectroscopy and transmission electron microscopy (TEM). Although PPG shows moderately hydrophilic character, the formation of nanosize polymeric micelles was confirmed by fluorescence and TEM studies. The low value of the critical aggregation concentration exhibited that the tendency for the formation of copolymer aggregates in aqueous solution was very high due to the strong hydrophobicity of the PHFBMA(145)-b-PPGA(33) block copolymer. The combination of DLS and SLS measurements revealed the existence of micellar aggregates in aqueous solution with an association number of approximately 40 +/- 7 for block copolymer micelles. It was also found in TEM observation that there are 40-50 micelles accumulated into one aggregate and these micelles are loosely packed inside the aggregate.
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In situ Analysis of North American Diamond: Implications for Diamond Growth Modeling
NASA Astrophysics Data System (ADS)
Schulze, D. J.; Van Rythoven, A. D.; Hauri, E.; Wang, J.
2014-12-01
Diamond crystals from three North American kimberlite occurrences were investigated with cathodoluminescence (CL) and secondary ion mass spectrometry (SIMS) to determine their growth history, carbon isotope composition and nitrogen content. Samples analyzed include sixteen from Lynx (Quebec), twelve from Kelsey Lake (Colorado) and eighteen from A154 South (Diavik mine, Northwest Territories). Growth histories for the samples vary from simple to highly complex based on their CL images and depending on the individual stone. Deformation lamellae are evident in CL images of the Lynx crystals which typically are brownish in color. Two to five points per diamond were analyzed by SIMS for carbon isotope composition (δ13CPDB) and three to seven points for nitrogen content. The results for the A154 South (δ13CPDB = -6.76 to -1.68 ‰) and Kelsey Lake (δ13CPDB = -11.81 to -2.43 ‰) stones (mixed peridotitic and eclogitic suites) are similar to earlier reported values. The Lynx kimberlite stones have anomalously high carbon isotope ratios and range from -3.58 to +1.74 ‰. The Lynx diamond suite is almost entirely peridotitic. The unusually high (i.e. >-5‰) δ13C values of the Lynx diamonds, as well as those from Wawa, Ontario and Renard, Quebec, may indicate an anomalous carbon reservoir for the Superior cratonic mantle relative to other cratons. In addition to the heavier carbon isotope values, the Lynx samples have very low nitrogen contents (<100 ppm). Nitrogen contents for Kelsey Lake and Diavik samples are more typical and range to ~1100 ppm. Comparison of observed core to rim variations in nitrogen content and carbon isotopes with modeled Rayleigh fractionation trends for published diamond growth mechanisms allows for evaluation of carbon speciation and other parent fluid conditions. Observed trends that closely follow modeled data are rare, but appear to suggest diamond growth from carbonate-bearing fluids at Lynx and Diavik, and growth from a methane-bearing fluid at Kelsey Lake. However the majority of crystals appear to have very complex growth histories that are clearly the result of multiple growth and resorption events. Trends observed in most of the samples from this study are chaotic and no consistent patterns are seen.
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Trifecta outcomes after robotic-assisted laparoscopic prostatectomy.
Shikanov, Sergey A; Zorn, Kevin C; Zagaja, Gregory P; Shalhav, Arieh L
2009-09-01
To evaluate the trifecta outcomes following robotic-assisted laparoscopic prostatectomy (RALP) and compare the results applying definitions of continence and potency as reported in the literature vs validated questionnaire. The trifecta rate of achieving continence, potency, and undetectable prostate-specific antigen (PSA) following radical prostatectomy has been estimated to be approximately 60% at 1-2 years in open radical prostatectomy series. The definitions of continence and potency were not standardized, which poses difficulty in comparing published results. A prospective, institutional RALP database was analyzed for preoperatively continent and potent men with >/= 1 year follow-up after bilateral nerve-sparing surgery. Continence and potency were evaluated preoperatively and at 3, 6, 12, and 24 months after surgery by surgeon interview (subjective) and using University of California Los-Angeles Prostate Cancer Index self-administered questionnaire (objective). Biochemical recurrence was defined as a detectable (> 0.05 ng/mL), increasing PSA on 2 consecutive tests. Among 1362 consecutive RALPs, 380 patients were preoperatively potent and continent underwent surgery with bilateral nerve-sparing technique and had sufficient follow-up. Trifecta rates applying subjective continence and potency definitions were 34%, 52%, 71%, and 76% at 3, 6, 12, and 24 months, respectively. The corresponding trifecta rates using objective continence and potency definitions stood at 16%, 31%, 44%, and 44%. The difference was statistically significant at each time point (P < .0001). RALP provides trifecta outcome rates comparable to open surgery. The outcome rates vary significantly depending on the tools used for continence and potency evaluation.
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NASA Astrophysics Data System (ADS)
Sturrock, Colin P.; Catlos, Elizabeth J.; Miller, Nathan R.; Akgun, Aykut; Fall, András; Gabitov, Rinat I.; Yilmaz, Ismail Omer; Larson, Toti; Black, Karen N.
2017-08-01
Six limestone assemblages along the North Anatolian Fault (NAF) Niksar pull-apart basin in northern Turkey were analyzed for δ18OPDB and δ13CPDB using bulk isotope ratio mass spectrometry (IRMS). Matrix-vein differences in δ18OPDB (-2.1 to 6.3‰) and δ13CPDB (-0.9 to 4.6‰) suggest a closed fluid system and rock buffering. Veins in one travertine and two limestone assemblages were further subjected to cathodoluminescence, trace element (Laser Ablation Inductively Coupled Plasma Mass Spectrometry) and δ18OPDB (Secondary Ion Mass Spectrometry, SIMS) analyses. Fluid inclusions in one limestone sample yield Th of 83.8 ± 7.3 °C (±1σ, mean average). SIMS δ18OPDB values across veins show fine-scale variations interpreted as evolving thermal conditions during growth and limited rock buffering seen at a higher-resolution than IRMS. Rare earth element data suggest calcite veins precipitated from seawater, whereas the travertine has a hydrothermal source. The δ18OSMOW-fluid for the mineralizing fluid that reproduces Th is +2‰, in range of Cretaceous brines, as opposed to negative δ18OSMOW-fluid from meteoric, groundwater, and geothermal sites in the region and highly positive δ18OSMOW-fluid expected for mantle-derived fluids. Calcite veins at this location do not record evidence for deeply-sourced metamorphic and magmatic fluids, an observation that differs from what is reported for the NAF elsewhere along strike.
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Kvenvolden, K.A.; Hostettler, F.D.; Carlson, P.R.; Rapp, J.B.; Threlkeld, C.N.; Warden, A.
1995-01-01
Although the shorelines of Prince William Sound still bear traces of the 1989 Exxon Valdez oil spill, most of the flattened tar balls that can be found today on these shorelines are not residues of Exxon Valdez oil. Instead, the carbon-isotopic and hydrocarbon-biomarker signatures of 61 tar ball samples, collected from shorelines throughout the northern and western parts of the sound, are all remarkably similar and have characteristics consistent with those of oil products that originated from the Monterey Formation source rocks of California. The carbon-isotopic compositions of the tar balls are all closely grouped (??13CPDB = -23.7 ?? 0.2???), within the range found in crude oils from those rocks, but are distinct from isotopic compositions of 28 samples of residues from the Exxon Valdez oil spill (??13CPDB = -29.4 ?? 0.1???). Likewise, values for selected biomarker ratios in the tar balls are all similar but distinct from values of residues from the 1989 oil spill. Carbon-isotopic and biomarker signatures generally relate the tar balls to oil products used in Alaska before ???1970 for construction and pavements. How these tar balls with such similar geochemical characteristics became so widely dispersed throughout the northern and western parts of the sound is not known with certainty, but the great 1964 Alaska earthquake was undoubtedly an important trigger, causing spills from ruptured storage facilities of California-sourced asphalt and fuel oil into Prince William Sound.
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Si, Wei; Wang, Xiumei; Liu, Huifang; Yu, Shenye; Li, Zhaoli; Chen, Liping; Zhang, Wanjiang; Liu, Siguo
2015-01-01
To construct a novel live, attenuated Salmonella vaccine, the lon, cpxR and cpdB genes were deleted from a wild-type Salmonella enterica serovar Enteritidis-6 (SM-6) strain using the phage λ Red homologous recombination system, resulting in SM-△CpxR, SM-△C/Lon and SM-△C/L/CpdB. The growth curves of strain SM-△C/Lon grew more rapidly than the other strains and had OD 600 values higher than the other strains starting at the 4 h time point. The growth curves of strain SM-△C/L/CpdB were relatively flat. The colonization time of SM-△C/L/CpdB is about 8-10 days. Deleting the lon/cpxR/cpdB (SM-6) genes resulted in an approximate 10(3)-fold attenuation in virulence assessed by the analysis of the LD50 of specific pathogen-free (SPF) chicks. This result indicated that the deletion of the lon, cpxR and cpdB genes induced significant virulence attenuation. The protective effects of SM-△C/L/CpdB vaccination in SPF chicks against 5 × 10(9) colony forming units (CFU) of S. Enteritidis were resulted from the induction of an effective immune response. These findings demonstrate the potential of mutant SM-△C/L/CpdB to be used as an effective vaccine. Copyright © 2015 Elsevier Ltd. All rights reserved.
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NASA Astrophysics Data System (ADS)
Noël, J.; Godard, M.; Martinez, I.; Oliot, E.; Williams, M. J.; Rodriguez, O.; Chaduteau, C.; Gouze, P.
2017-12-01
Carbon trapping in ophiolitic peridotites contributes to the global carbon cycle between solid Earth and its outer envelopes (through subduction and/or modern alteration). To investigate this process, we performed petro-structural (microtomography, EBSD, EPMA) and geochemical studies (LA-ICP-MS, carbon and oxygen isotopes on bulk and minerals using SHRIMP) of harzburgites cored in the Oman Ophiolite. Studied harzburgites are highly serpentinized (> 90 %) and crosscut by 3 generations of carbonates (> 20 Vol%) with compositions from calcite to dolomite (Mg/Ca = 0-0.85). Type 1 carbonates are fine penetrative veinlets and mesh core after olivine. They have low REE (e.g., Yb = 0.08-0.23 x CI-chondrite) and negative Ce anomalies. They have δ13CPDB = -15.2 to 1.10‰ and δ18OSMOW = 17.5 to 33.7‰, suggesting precipitation temperatures up to 110°C. Type 2 carbonates are pluri-mm veins bounded by cm-thick serpentinized vein selvages, oriented dominantly parallel to mantle foliation. Dynamic recrystallization is observed, indicating polygenetic formation: well crystallized calcite with REE abundances similar to Type 1 carbonates are locally replaced by small dolomite and calcite grains with higher REE (e.g., Yb = 0.35-1.0 x CI-chondrite) and positive Gd anomaly. Type 2 carbonates have δ13CPDB = -12.6 to -4.1‰ and δ18OSMOW = 25.0 to 32.7‰, suggesting precipitation temperatures from 10 to 60°C. Type 3 carbonates are late pluri-mm to cm veins reactivating Type 2 veins. They consist of small grains of dolomite and calcite with REE abundances similar to recrystallized Type 2 carbonates. Type 3 carbonates have δ13CPDB = -8.3 to -5.8‰ and δ18OSMOW = 28.8 to 32.7‰, suggesting precipitation temperatures <35°C. δ13C data indicate an evolution of fluid composition precipitating carbonates from seawater- and sediment-derived fluids to meteoric water. Carbonate formation starts during oceanic lithospheric cooling and occurs as a penetrative process at the expense of olivine (Type 1, at T > 100°C). Formation of carbonate veins (Type 2) indicates localization of fluid flux, while serpentinization remains the dominant alteration process. Low T carbonate veins (Type 3) remain the main flow path through ophiolitic peridotites. Our study suggests that their orientation is controlled by the later stages of oceanic mantle deformation.
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Ab Initio Design of Potent Anti-MRSA Peptides based on Database Filtering Technology
Mishra, Biswajit; Wang, Guangshun
2012-01-01
To meet the challenge of antibiotic resistance worldwide, a new generation of antimicrobials must be developed.1 This communication demonstrates ab initio design of potent peptides against methicillin-resistant Staphylococcus aureus (MRSA). Our idea is that the peptide is very likely to be active when most probable parameters are utilized in each step of the design. We derived the most probable parameters (e.g. amino acid composition, peptide hydrophobic content, and net charge) from the antimicrobial peptide database2 by developing a database filtering technology (DFT). Different from classic cationic antimicrobial peptides usually with high cationicity, DFTamP1, the first anti-MRSA peptide designed using this technology, is a short peptide with high hydrophobicity but low cationicity. Such a molecular design made the peptide highly potent. Indeed, the peptide caused bacterial surface damage and killed community-associated MRSA USA300 in 60 minutes. Structural determination of DFTamP1 by NMR spectroscopy revealed a broad hydrophobic surface, providing a basis for its potency against MRSA known to deploy positively charged moieties on the surface as a mechanism for resistance. A combination of our ab initio design with database screening3 led to yet another peptide with enhanced potency. Because of simple composition, short length, stability to proteases, and membrane targeting, the designed peptides are attractive leads for developing novel anti-MRSA therapeutics. Our database-derived design concept can be applied to the design of peptide mimicries to combat MRSA as well. PMID:22803960
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Ab initio design of potent anti-MRSA peptides based on database filtering technology.
Mishra, Biswajit; Wang, Guangshun
2012-08-01
To meet the challenge of antibiotic resistance worldwide, a new generation of antimicrobials must be developed. This communication demonstrates ab initio design of potent peptides against methicillin-resistant Staphylococcus aureus (MRSA). Our idea is that the peptide is very likely to be active when the most probable parameters are utilized in each step of the design. We derived the most probable parameters (e.g., amino acid composition, peptide hydrophobic content, and net charge) from the antimicrobial peptide database by developing a database filtering technology (DFT). Different from classic cationic antimicrobial peptides usually with high cationicity, DFTamP1, the first anti-MRSA peptide designed using this technology, is a short peptide with high hydrophobicity but low cationicity. Such a molecular design made the peptide highly potent. Indeed, the peptide caused bacterial surface damage and killed community-associated MRSA USA300 in 60 min. Structural determination of DFTamP1 by NMR spectroscopy revealed a broad hydrophobic surface, providing a basis for its potency against MRSA known to deploy positively charged moieties on the surface as a mechanism for resistance. Our ab initio design combined with database screening led to yet another peptide with enhanced potency. Because of the simple composition, short length, stability to proteases, and membrane targeting, the designed peptides are attractive leads for developing novel anti-MRSA therapeutics. Our database-derived design concept can be applied to the design of peptide mimicries to combat MRSA as well.
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Sarma, Amy; Cannon, Christopher P; de Lemos, James; Rouleau, Jean L; Lewis, Eldrin F; Guo, Jianping; Mega, Jessica L; Sabatine, Marc S; O'Donoghue, Michelle L
2014-05-01
Observational studies have raised concerns that high-potency statins increase the risk of acute kidney injury. We therefore examined the incidence of kidney injury across 2 randomized trials of statin therapy. PROVE IT-TIMI 22 enrolled 4162 subjects after an acute coronary syndrome (ACS) and randomized them to atorvastatin 80 mg/day versus pravastatin 40 mg/day. A-to-Z enrolled 4497 subjects after ACS and randomized them to a high-potency (simvastatin 40 mg/day × 1 months, then simvastatin 80 mg/day) versus a delayed moderate-potency statin strategy (placebo × 4 months, then simvastatin 20 mg/day). Serum creatinine was assessed centrally at serial time points. Adverse events (AEs) relating to kidney injury were identified through database review. Across both trials, mean serum creatinine was similar between treatment arms at baseline and throughout follow-up. In A-to-Z, the incidence of a 1.5-fold or ≥ 0.3 mg/dL rise in serum creatinine was 11.4% for subjects randomized to a high-potency statin regimen versus 12.4% for those on a delayed moderate-potency regimen (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.76 to 1.10; P=0.33). In PROVE IT-TIMI 22, the incidence was 9.4% for subjects randomized to atorvastatin 80 mg/day and 10.6% for subjects randomized to pravastatin 40 mg/day (OR, 0.88; 95% CI, 0.71 to 1.09; P=0.25). Consistent results were observed for different kidney injury thresholds and in individuals with diabetes mellitus or with moderate renal dysfunction. The incidence of kidney injury-related adverse events (AEs) was not statistically different for patients on a high-potency versus moderate-potency statin regimen (OR, 1.06; 95% CI, 0.68 to 1.67; P=0.78). For patients enrolled in 2 large randomized trials of statin therapy after ACS, the use of a high-potency statin regimen did not increase the risk of kidney injury.
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Dual deep modeling: multi-level modeling with dual potencies and its formalization in F-Logic.
Neumayr, Bernd; Schuetz, Christoph G; Jeusfeld, Manfred A; Schrefl, Michael
2018-01-01
An enterprise database contains a global, integrated, and consistent representation of a company's data. Multi-level modeling facilitates the definition and maintenance of such an integrated conceptual data model in a dynamic environment of changing data requirements of diverse applications. Multi-level models transcend the traditional separation of class and object with clabjects as the central modeling primitive, which allows for a more flexible and natural representation of many real-world use cases. In deep instantiation, the number of instantiation levels of a clabject or property is indicated by a single potency. Dual deep modeling (DDM) differentiates between source potency and target potency of a property or association and supports the flexible instantiation and refinement of the property by statements connecting clabjects at different modeling levels. DDM comes with multiple generalization of clabjects, subsetting/specialization of properties, and multi-level cardinality constraints. Examples are presented using a UML-style notation for DDM together with UML class and object diagrams for the representation of two-level user views derived from the multi-level model. Syntax and semantics of DDM are formalized and implemented in F-Logic, supporting the modeler with integrity checks and rich query facilities.
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A Drug Discovery Partnership for Personalized Breast Cancer Therapy
2012-09-01
flexible searches of compound databases using detailed pharmacophore and CoMFA QSAR results. (Months 9-24). 1,3,8-trihydroxyanthraquinone was taken...Cytochrome P450 Inhibitors- A Study of Their Potency and Selectivity”, J. Sridhar, J. Liu, C.L.K. Stevens, and M. Foroozesh, Society of Toxicology
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EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of polycyclic aromatic hydrocarbon (PAH) mixtures that when finalized will appear on the Integrated Risk Information System (IRIS) database. ...
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DEVELOPMENT OF A REFINED DATABASE OF MAMMALIAN RELATIVE POTENCY ESTIMATES FOR DIOXIN-LIKE COMPOUNDS
The toxic equivalency factor (TEF) approach has been widely accepted as the most feasible method available at present for evaluating potential health risks associated with exposure to mixtures of dioxin-like compounds (DLCs). The current mammalian TEFs for the DLCs were establis...
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Finley, David S; Chang, Alexandra; Morales, Blanca; Osann, Kathryn; Skarecky, Douglas; Ahlering, Thomas
2010-07-01
This is the third publication that updates clinical outcomes using a novel technique to apply locoregional hypothermia to the pelvis during robot-assisted radical prostatectomy (RARP) to reduce inflammatory injury. This report updates urinary and sexual clinical outcomes with a minimum of 1 year follow-up. Regional pelvic cooling (<30 degrees C) [corrected] was achieved with a prototype endorectal cooling balloon (ECB) during the course ofRARP. All clinical data were entered prospectively into an electronic database for historic (cases 1-666) and hypothermic groups (115 pts). Urinary and sexual outcomes were obtained using self-administered validated questionnaires. Continence was defined as no pads, and potency was defined as two affirmative answers to "erections adequate for penetration" and "were the erections satisfactory." Six patients were excluded: three ECB malfunction, three previous radiation/surgery. Median time to zero pad use was 39 days vs 62 days (hypothermic vs controls, P = 0.0003). At 1 year, overall pad-free continence was 96.3% (105/109) vs controls of 86.6%, P < 0.001. Potency was evaluated in all men (40-78 years) with preoperative International Index of Erectile Function-5 scores of 22 to 25. At 3 months, potency results were unchanged between groups: 24% vs 23%. At 15 months, the potency rates were significantly better for the hypothermic group, 83% vs controls 66%, P = 0.045. No difference in oncologic outcome was noted with cooling. Using a prototype cooling balloon, hypothermic RARP significantly improved time to continence and overall continence. Hypothermia also resulted in a modest but statistically significant improvement in potency at 15 months. Once cooling parameters have been optimized, a randomized multicenter clinical trial will be needed for validation.
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A Web Server and Mobile App for Computing Hemolytic Potency of Peptides.
Chaudhary, Kumardeep; Kumar, Ritesh; Singh, Sandeep; Tuknait, Abhishek; Gautam, Ankur; Mathur, Deepika; Anand, Priya; Varshney, Grish C; Raghava, Gajendra P S
2016-03-08
Numerous therapeutic peptides do not enter the clinical trials just because of their high hemolytic activity. Recently, we developed a database, Hemolytik, for maintaining experimentally validated hemolytic and non-hemolytic peptides. The present study describes a web server and mobile app developed for predicting, and screening of peptides having hemolytic potency. Firstly, we generated a dataset HemoPI-1 that contains 552 hemolytic peptides extracted from Hemolytik database and 552 random non-hemolytic peptides (from Swiss-Prot). The sequence analysis of these peptides revealed that certain residues (e.g., L, K, F, W) and motifs (e.g., "FKK", "LKL", "KKLL", "KWK", "VLK", "CYCR", "CRR", "RFC", "RRR", "LKKL") are more abundant in hemolytic peptides. Therefore, we developed models for discriminating hemolytic and non-hemolytic peptides using various machine learning techniques and achieved more than 95% accuracy. We also developed models for discriminating peptides having high and low hemolytic potential on different datasets called HemoPI-2 and HemoPI-3. In order to serve the scientific community, we developed a web server, mobile app and JAVA-based standalone software (http://crdd.osdd.net/raghava/hemopi/).
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Endolithic Boring Enhance the Deep-sea Carbonate Lithification on the Southwest Indian Ridge
NASA Astrophysics Data System (ADS)
Peng, X.; Xu, H.
2017-12-01
Deep-sea carbonates represent an important type of sedimentary rock due to their effect on the composition of upper oceanic crust and their contribution to deep-sea geochemical cycles. However, the lithification of deep-sea carbonates at the seafloor has remained a mystery for many years. A large lithified carbonate area, characterized by thriving benthic faunas and tremendous amount of endolithic borings, was discovered in 2008, blanketed on the seafloor of ultraslow spreading Southwest Indian Ridge (SWIR). Macrofaunal inhabitants including echinoids, polychaetes, gastropods as well as crustaceans, are abundant in the sample. The most readily apparent feature of the sample is the localized enhancement of density around the borings. The boring features of these carbonate rocks and factors that may enhance deep-sea carbonate lithification are reported. The δ13CPDB values of 46 bulk samples are -0.37 to 1.86‰, while these samples have a relatively narrow δ18OPDB range of 1.35 to 3.79‰. The bulk δ13CPDB values of chalk and gray excrements are positively correlated with bulk δ18OPDB values (r = 0.91) (Fig. 8), which reflects that endolithic boring is possibly a critical factor influence the lithification. We suggest that active boring may trigger the dissolution of the original calcite and thus accelerate deep-sea carbonate lithification on mid-ocean ridges. Our study reports an unfamiliar phenomenon of non-burial carbonate lithification and interested by the observation that it is often associated with boring feature. These carbonate rocks may provide a novel mechanism for deep-sea carbonate lithification at the deep-sea seafloor and also illuminate the geological and biological importance of deep-sea carbonate rocks on mid-ocean ridges.
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The toxic equivalency factor (TEF) approach has been widely accepted as the most feasible and plausible method presently available for evaluating potential health risks associated with exposure to mixtures of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofuran...
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A Web Server and Mobile App for Computing Hemolytic Potency of Peptides
NASA Astrophysics Data System (ADS)
Chaudhary, Kumardeep; Kumar, Ritesh; Singh, Sandeep; Tuknait, Abhishek; Gautam, Ankur; Mathur, Deepika; Anand, Priya; Varshney, Grish C.; Raghava, Gajendra P. S.
2016-03-01
Numerous therapeutic peptides do not enter the clinical trials just because of their high hemolytic activity. Recently, we developed a database, Hemolytik, for maintaining experimentally validated hemolytic and non-hemolytic peptides. The present study describes a web server and mobile app developed for predicting, and screening of peptides having hemolytic potency. Firstly, we generated a dataset HemoPI-1 that contains 552 hemolytic peptides extracted from Hemolytik database and 552 random non-hemolytic peptides (from Swiss-Prot). The sequence analysis of these peptides revealed that certain residues (e.g., L, K, F, W) and motifs (e.g., “FKK”, “LKL”, “KKLL”, “KWK”, “VLK”, “CYCR”, “CRR”, “RFC”, “RRR”, “LKKL”) are more abundant in hemolytic peptides. Therefore, we developed models for discriminating hemolytic and non-hemolytic peptides using various machine learning techniques and achieved more than 95% accuracy. We also developed models for discriminating peptides having high and low hemolytic potential on different datasets called HemoPI-2 and HemoPI-3. In order to serve the scientific community, we developed a web server, mobile app and JAVA-based standalone software (http://crdd.osdd.net/raghava/hemopi/).
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Review of the use of high potencies in basic research on homeopathy.
Clausen, Jürgen; van Wijk, Roeland; Albrecht, Henning
2011-10-01
The HomBRex database includes details of about 1500 basic research experiments in homeopathy. A general overview on the experiments listed in the HomBRex database is presented, focusing on high dilutions and the different settings in which those were used. Though often criticised, many experiments with remedies diluted beyond Avogadro's number demonstrate specific effects. A total of 830 experiments employing high potencies was found; in 745 experiments of these (90%), at least one positive result was reported. Animals represent the most often used model system (n=371), followed by plants (n=201), human material (n=92), bacteria and viruses (n=37) and fungi (n=32). Arsenicum album (Ars.) is the substance most often applied (n=101), followed by Sulphur (Sulph.) and Thuja (Thuj.) (n=65 and 48, respectively). Proving, prophylactic and therapeutic study designs have all been used and appear appropriate for homeopathy basic research using high dilutions. The basic research data set to support specific effects unique to high dilutions and opposite to those observed with low dilutions is, to date, insufficient. Copyright © 2011 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.
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Hu, Jia; Judge, Timothy A
2017-06-01
Integrating the leader trait perspective with dominance complementarity theory, we propose team power distance as an important boundary condition for the indirect impact of leader extraversion, agreeableness, and conscientiousness on team performance through a team's potency beliefs and through relational identification with the leader. Using time-lagged, 3-source data from 71 teams, we found that leader extraversion had a positive indirect impact on team in-role and extrarole performance through relational identification, but only for high power distance teams; leader conscientiousness had a positive influence on team in-role performance through team potency, but only for high power distance teams; and leader agreeableness had a positive effect on team in-role and extrarole performance via relational identification and on team in-role performance via team potency, but only for low power distance teams. The findings address prior inconsistencies regarding the relationships between leader traits and team effectiveness, identify an important boundary condition and key team processes that bridge the links, and provide a deeper understanding of the role of leader traits in teams. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
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NASA Astrophysics Data System (ADS)
Reis, A.; McGlue, M. M.; Waite, L.; Erhardt, A. M.
2017-12-01
Diagenetic processes influenced by changing climate, eustatic fluctuations, and porewater evolution led to the formation and alteration of carbonate layers in the Pennsylvanian Wolfcamp D Formation of the Midland Basin. Preliminary evidence from bulk geochemistry, oxygen and carbon stable isotopes, and petrographic analysis of the carbonates recovered from two drill cores indicate multiple generations of diagenesis. High Mg calcite and dolomite layers predominantly occur in the fine grained intervals of both cores. Whereas there are less carbonate layers in the central basin core, more of the layers underwent diagenesis compared to the carbonates in the southern core. δ13CPDB values ranging from -6‰ to -4‰ and the presence of framboidal pyrite indicate initial dolomite precipitation occurring in the zone of bacterial sulfate reduction. Later stages alteration occurred following the burial diagenesis of clay, releasing Mg2+ and Fe2+ into the pore waters allowing ferroan dolomite rims to precipitate on the precursor iron-poor dolomite rhombs. δ13CPDB and δ18OPDBvalues from altered beds in the southern core show a positive 4-6‰ offset from the central basin beds. Petrographic analysis of the carbonate intervals shows a larger allochem size, and lower pyrite abundance in the southern core. These differences can be associated with a shorter source-to-sink distance and less frequent bottom water anoxia, leading to reduced rates of sulfate reduction. One possibility we will explore is if increased circulation due to the proximity of the southern core to the Sheffield Channel could stabilize the bottom water conditions in this region of the basin. In addition to dolomite precipitation and replacement, scanning electron microscopy reveals the replacement of silica cements by calcite, suggesting an increase in porewater pH during or following sulfate reduction coinciding with pyrite formation. Changing bottom water chemistry tied to fluctuations in sea-level through time led to porewater conditions favorable to several generations of post-depositional diagenesis.
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Galipeau, Jacques; Krampera, Mauro; Barrett, John; Dazzi, Francesco; Deans, Robert J; DeBruijn, Joost; Dominici, Massimo; Fibbe, Willem E; Gee, Adrian P; Gimble, Jeffery M; Hematti, Peiman; Koh, Mickey B C; LeBlanc, Katarina; Martin, Ivan; McNiece, Ian K; Mendicino, Michael; Oh, Steve; Ortiz, Luis; Phinney, Donald G; Planat, Valerie; Shi, Yufang; Stroncek, David F; Viswanathan, Sowmya; Weiss, Daniel J; Sensebe, Luc
2016-02-01
Mesenchymal stromal cells (MSCs) as a pharmaceutical for ailments characterized by pathogenic autoimmune, alloimmune and inflammatory processes now cover the spectrum of early- to late-phase clinical trials in both industry and academic sponsored studies. There is a broad consensus that despite different tissue sourcing and varied culture expansion protocols, human MSC-like cell products likely share fundamental mechanisms of action mediating their anti-inflammatory and tissue repair functionalities. Identification of functional markers of potency and reduction to practice of standardized, easily deployable methods of measurements of such would benefit the field. This would satisfy both mechanistic research as well as development of release potency assays to meet Regulatory Authority requirements for conduct of advanced clinical studies and their eventual registration. In response to this unmet need, the International Society for Cellular Therapy (ISCT) addressed the issue at an international workshop in May 2015 as part of the 21st ISCT annual meeting in Las Vegas. The scope of the workshop was focused on discussing potency assays germane to immunomodulation by MSC-like products in clinical indications targeting immune disorders. We here provide consensus perspective arising from this forum. We propose that focused analysis of selected MSC markers robustly deployed by in vitro licensing and metricized with a matrix of assays should be responsive to requirements from Regulatory Authorities. Workshop participants identified three preferred analytic methods that could inform a matrix assay approach: quantitative RNA analysis of selected gene products; flow cytometry analysis of functionally relevant surface markers and protein-based assay of secretome. We also advocate that potency assays acceptable to the Regulatory Authorities be rendered publicly accessible in an "open-access" manner, such as through publication or database collection. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
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Sweetness prediction of natural compounds.
Chéron, Jean-Baptiste; Casciuc, Iuri; Golebiowski, Jérôme; Antonczak, Serge; Fiorucci, Sébastien
2017-04-15
Based on the most exhaustive database of sweeteners with known sweetness values, a new quantitative structure-activity relationship model for sweetness prediction has been set up. Analysis of the physico-chemical properties of sweeteners in the database indicates that the structure of most potent sweeteners combines a hydrophobic scaffold functionalized by a limited number of hydrogen bond sites (less than 4 hydrogen bond donors and 10 acceptors), with a moderate molecular weight ranging from 350 to 450g·mol -1 . Prediction of sweetness, bitterness and toxicity properties of the largest database of natural compounds have been performed. In silico screening reveals that the majority of the predicted natural intense sweeteners comprise saponin or stevioside scaffolds. The model highlights that their sweetness potency is comparable to known natural sweeteners. The identified compounds provide a rational basis to initiate the design and chemosensory analysis of new low-calorie sweeteners. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Schiavina, R; Borghesi, M; Dababneh, H; Pultrone, C V; Chessa, F; Concetti, S; Gentile, G; Vagnoni, V; Romagnoli, D; Della Mora, L; Rizzi, S; Martorana, G; Brunocilla, E
2014-12-01
To offer a comprehensive account of surgical outcomes on a defined series of patients treated with radical retropubic prostatectomy (RRP) for prostate cancer in a single European Center after 5-year minimum follow-up according to the Survival, Continence and Potency (SCP) system. We evaluated our Institutional database of patients who underwent RRP from November 1995 to September 2008. Oncological and functional outcomes were reported according to the recently proposed SCP system. The 5- and 10-year biochemical recurrence-free survival rates were 80.1% and 55.8%, respectively. At the end of follow-up, 611 (78.5%) patients were fully continent (C0), 107 (13.8%) used 1 pad for security (C1) and 60 (7.7%) patients were incontinent (C2). Of the 112 patients who underwent nerve-sparing RRP, 22 (19.6%) were fully potent without aids (P0), 13 (11.6%) were potent with assumption of PDE-5 inhibitors (P1) and 77 (68.8%) experienced erectile dysfunction (P2). The combined SCP outcomes were reported together only in 95 (12.2%) evaluable patients. In patients preoperatively continent and potent, who received a nerve-sparing and did not require adjuvant therapy, oncological and functional success was attained by 29 (30.5%) patients. In the subgroup of 508 patients not evaluable for potency recovery, oncological and continence outcomes were obtained in 357 patients (70.3%). Survival, Continence and Potency (SCP) classification offer a comprehensive report of surgical results, even in those patients who do not represent the best category, thus allowing to provide a much more accurate evaluation of outcomes after RP. Copyright © 2014 Elsevier Ltd. All rights reserved.
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EUV lithographic radiation grafting of thermo-responsive hydrogel nanostructures
NASA Astrophysics Data System (ADS)
Farquet, Patrick; Padeste, Celestino; Solak, Harun H.; Gürsel, Selmiye Alkan; Scherer, Günther G.; Wokaun, Alexander
2007-12-01
Nanostructures of the thermoresponsive poly( N-isopropyl acrylamide) (PNIPAAm) and of PNIPAAm-block-poly(acrylic acid) copolymers were produced on poly(tetrafluoroethylene-co-ethyelene) (ETFE) films using extreme ultraviolet (EUV) lithographic exposure with subsequent graft-polymerization. The phase transition of PNIPAAm nanostructures at the low critical solution temperature (LCST) at 32 °C was imaged by atomic force microscopy (AFM) phase contrast measurements in pure water. Results show a higher phase contrast for samples measured below the LCST temperature than for samples above the LCST, proving that the soft PNIPAAm hydrogel transforms into a much more compact conformation above the LCST. EUV lithographic exposures were combined with the reversible addition-fragment chain transfer (RAFT)-mediated polymerization using cyanoisopropyl dithiobenzoate (CPDB) as chain transfer agent to synthesize PNIPAAm block-copolymer nanostructures.
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2012-01-01
Background Drugs safety issues are now recognized as being factors generating the most reasons for drug withdrawals at various levels of development and at the post-approval stage. Among them cardiotoxicity remains the main reason, despite the substantial effort put into in vitro and in vivo testing, with the main focus put on hERG channel inhibition as the hypothesized surrogate of drug proarrhythmic potency. The large interest in the IKr current has resulted in the development of predictive tools and informative databases describing a drug's susceptibility to interactions with the hERG channel, although there are no similar, publicly available sets of data describing other ionic currents driven by the human cardiomyocyte ionic channels, which are recognized as an overlooked drug safety target. Discussion The aim of this database development and publication was to provide a scientifically useful, easily usable and clearly verifiable set of information describing not only IKr (hERG), but also other human cardiomyocyte specific ionic channels inhibition data (IKs, INa, ICa). Summary The broad range of data (chemical space and in vitro settings) and the easy to use user interface makes tox-database.net a useful tool for interested scientists. Database URL http://tox-database.net. PMID:22947121
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Contrasting fault fluids along high-angle faults: a case study from Southern Apennines (Italy)
NASA Astrophysics Data System (ADS)
Sinisi, Rosa; Petrullo, Angela Vita; Agosta, Fabrizio; Paternoster, Michele; Belviso, Claudia; Grassa, Fausto
2016-10-01
This work focuses on two fault-controlled deposits, the Atella and Rapolla travertines, which are associated with high-angle extensional faults of the Bradano Trough, southern Apennines (Italy). The Atella travertine is along a NW-SE striking, deep-seated extensional fault, already described in literature, which crosscuts both Apulian carbonates and the overlying foredeep basin infill. The Rapolla travertine is on top of a NE-SW striking, shallow-seated fault, here described for the first time, which is interpreted as a tear fault associated with a shallow thrust displacing only the foredeep basin infill. The results of structural, sedimentological, mineralogical, and C and O isotope analyses are here reported and discussed to assess the provenance of mineralizing fluids, and to evaluate the control exerted by the aforementioned extensional faults on deep, mantle-derived and shallow, meteoric fluids. Sedimentological analysis is consistent with five lithofacies in the studied travertines, which likely formed in a typical lacustrine depositional environment. Mineralogical analysis show that travertines mainly consist of calcite, and minor quartz, feldspar and clay minerals, indicative of a terrigenous supply during travertine precipitation. The isotope signature of the two studied travertines shows different provenance for the mineralizing fluids. At the Atella site, the δ13CPDB values range between + 5.2 and + 5.7‰ and the δ18OPDB values between - 9.0 and - 7.3‰, which are consistent with a mantle-derived CO2 component in the fluid. In contrast, at the Rapolla site the δ13CPDB values vary from - 2.7 to + 1.5‰ and the δ18OPDB values from - 6.8 to - 5.4‰, suggesting a mixed CO2 source with both biogenic-derived and mantle-derived fluids. The results of structural analyses conducted along the footwall damage zone of the fault exposed at the Rapolla site, show that the whole damage zone, in which fractures and joints likely channeled the mixed fluids, acted as a distributed conduit for both fault-parallel and cross-fault fluid migration.
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Garvie, Laurence A J; Knauth, L Paul; Bungartz, Frank; Klonowski, Stan; Nash, Thomas H
2008-08-01
Verrucaria rubrocincta Breuss is an endolithic lichen that inhabits caliche plates exposed on the surface of the Sonoran Desert. Caliche surface temperatures are regularly in excess of 60 degrees C during the summer and approach 0 degrees C in the winter. Incident light intensities are high, with photosynthetically active radiation levels typically to 2,600 micromol/m(2) s(-1) during the summer. A cross-section of rock inhabited by V. rubrocincta shows an anatomical zonation comprising an upper micrite layer, a photobiont layer containing clusters of algal cells, and a pseudomedulla embedded in the caliche. Hyphae of the pseudomedulla become less numerous with depth below the rock surface. Stable carbon and oxygen isotopic data for the caliche and micrite fall into two sloping, well-separated arrays on a delta(13)C-delta(18)O plot. The delta(13)C(PDB) of the micrite ranges from 2.1 to 8.1 and delta(18)O(SMOW) from 25.4 to 28.9, whereas delta(13)C(PDB) of the caliche ranges from -4.7 to 0.7 and delta(18)O(SMOW) from 23.7 to 29.2. The isotopic data of the micrite can be explained by preferential fixing of (12)C into the alga, leaving local (13)C enrichment and evaporative enrichment of (18)O in the water. The (14)C dates of the micrite range from recent to 884 years b.p., indicating that "dead" carbon from the caliche is not a significant source for the lichen-precipitated micrite. The endolithic growth is an adaptation to the environmental extremes of exposed rock surfaces in the hot desert. The micrite layer is highly reflective and reduces light intensity to the algae below and acts as an efficient sunscreen that blocks harmful UV radiation. The micrite also acts as a cap to the lichen and helps trap moisture. The lichen survives by the combined effects of biodeterioration and biomineralization. Biodeterioration of the caliche concomitant with biomineralization of a protective surface coating of micrite results in the distinctive anatomy of V. rubrocincta.
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CHEMICAL STRUCTURE INDEXING OF TOXICITY DATA ON ...
Standardized chemical structure annotation of public toxicity databases and information resources is playing an increasingly important role in the 'flattening' and integration of diverse sets of biological activity data on the Internet. This review discusses public initiatives that are accelerating the pace of this transformation, with particular reference to toxicology-related chemical information. Chemical content annotators, structure locator services, large structure/data aggregator web sites, structure browsers, International Union of Pure and Applied Chemistry (IUPAC) International Chemical Identifier (InChI) codes, toxicity data models and public chemical/biological activity profiling initiatives are all playing a role in overcoming barriers to the integration of toxicity data, and are bringing researchers closer to the reality of a mineable chemical Semantic Web. An example of this integration of data is provided by the collaboration among researchers involved with the Distributed Structure-Searchable Toxicity (DSSTox) project, the Carcinogenic Potency Project, projects at the National Cancer Institute and the PubChem database. Standardizing chemical structure annotation of public toxicity databases
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'Trifecta' after radical prostatectomy: is there a standard definition?
Borregales, Leonardo D; Berg, William T; Tal, Oded; Wambi, Chris; Kaufman, Sarah; Gaya, Jose M; Urzúa, Cristian; Badani, Ketan K
2013-07-01
To determine the extent of variability in the definitions of the 'trifecta' after radical prostatectomy (undetectable PSA, urinary continence and potency) to be found in the literature. To establish a consensus definition of the trifecta in an effort to standardize criteria and reporting. A systematic review of published articles found in the PubMed database for the period from January 2003 to March 2012 was performed. The search queries included the keywords 'radical prostatectomy,' 'prostatectomy outcome,' and 'trifecta'. A total of 86 publications were identified of which 14 were used for analysis. Eight different definitions of biochemical recurrence were reported, the most common definition being PSA ≥0.2 ng/mL. The definition of potency was the most variable. Ten different definitions of potency were found, with the most common being 'having erections sufficient for intercourse with or without a phosphodiesterase-5 inhibitor'. Nine different definitions of continence were found. The most common definition of continence was 'wearing no pads'. Only six of the 14 articles used validated questionnaires in their outcome measures. The definitions of trifecta reported in the literature are highly variable. We propose the following consensus definition based on our analysis: (1) PSA >0.2 ng/mL with confirmatory value; (2) attainment of erections sufficient for intercourse with or without oral pharmacological agents; (3) wearing zero pads. This consensus definition should be considered when designing studies and reporting outcomes of radical prostatectomy. © 2013 BJU International.
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Stevia (Stevia rebaudiana) a bio-sweetener: a review.
Goyal, S K; Samsher; Goyal, R K
2010-02-01
Studies revealed that Stevia has been used throughout the world since ancient times for various purposes; for example, as a sweetener and a medicine. We conducted a systematic literature review to summarize and quantify the past and current evidence for Stevia. We searched relevant papers up to 2007 in various databases. As we know that the leaves of Stevia plants have functional and sensory properties superior to those of many other high-potency sweeteners, Stevia is likely to become a major source of high-potency sweetener for the growing natural food market in the future. Although Stevia can be helpful to anyone, there are certain groups who are more likely to benefit from its remarkable sweetening potential. These include diabetic patients, those interested in decreasing caloric intake, and children. Stevia is a small perennial shrub that has been used for centuries as a bio-sweetener and for other medicinal uses such as to lower blood sugar. Its white crystalline compound (stevioside) is the natural herbal sweetener with no calories and is over 100-300 times sweeter than table sugar.
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FDA perspective on specifications for biotechnology products--from IND to PLA.
Murano, G
1997-01-01
Quality standards are obligatory throughout development, approval and post-marketing phases of biotechnology-derived products, thus assuring product identity, purity, and potency/strength. The process of developing and setting specifications should be based on sound science and should represent a logical progression of actions based on the use of experiential data spanning manufacturing process validation, consistency in production, and characterization of relevant product properties/attributes, by multiple analytical means. This interactive process occurs in phases, varying in rigour. It is best described as encompassing a framework which starts with the implementation of realistic/practical operational quality limits, progressing to the establishment/adoption of more stringent specifications. The historical database is generated from preclinical, toxicology and early clinical lots. This supports the clinical development programme which, as it progresses, allows for further assay method validation/refinement, adoption/addition due to relevant or newly recognized product attributes or rejection due to irrelevance. In the next phase, (licensing/approval) specifications are set through extended experience and validation of both the preparative and analytical processes, to include availability of suitable reference standards and extensive product characterization throughout its proposed dating period. Subsequent to product approval, the incremental database of test results serves as a natural continuum for further evolving/refining specifications. While there is considerable latitude in the kinds of testing modalities finally adopted to establish product quality on a routine basis, for both drugs and drug products, it is important that the selection takes into consideration relevant (significant) product characteristics that appropriately reflect on identity, purity and potency.
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Morimoto, K; Kimura, M; Murata, T; Imai, Y; Ookami, N; Igarashi, T; Kanoh, N; Kaminuma, T; Hayashi, Y
1994-01-01
Many carcinogens react with DNA and form critical DNA adducts, such as O6-alkylguanine (O6-AG), O4-alkylthymine (O4-AT), and 8-hydroxyguanine (8-OHG). This study provides a database that can be used for molecular dosimetry of these DNA adducts. A literature survey on DNA binding in vivo was done by the Dialog search from the MEDLINE database. We propose a Critical Covalent Binding Index (CCBI) for the assessment of in vivo DNA binding level (expressed as micro mol chemical bound per mol G or T/mmol chemical administered per kg body weight). The number of records and compounds in parenthesis of O6-AG, O4-AT, and 8-OHG were 245(13), 54(4), 79(15), respectively. Since the CCBI values for N-nitrosamine in target organ were higher than for non-target organ, they may provide a useful index for estimation of target organ site and carcinogenic potency. As a case example, CCBI values for O4-AT from animal data were applied for diethylnitrosamine human exposure estimation by diethylnitrosamine.
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Kun, Sándor; Begum, Jaida; Kyriakis, Efthimios; Stamati, Evgenia C V; Barkas, Thomas A; Szennyes, Eszter; Bokor, Éva; Szabó, Katalin E; Stravodimos, George A; Sipos, Ádám; Docsa, Tibor; Gergely, Pál; Moffatt, Colin; Patraskaki, Myrto S; Kokolaki, Maria C; Gkerdi, Alkistis; Skamnaki, Vassiliki T; Leonidas, Demetres D; Somsák, László; Hayes, Joseph M
2018-03-10
3-(β-d-Glucopyranosyl)-5-substituted-1,2,4-triazoles have been revealed as an effective scaffold for the development of potent glycogen phosphorylase (GP) inhibitors but with the potency very sensitive to the nature of the alkyl/aryl 5-substituent (Kun et al., Eur. J. Med. Chem. 2014, 76, 567). For a training set of these ligands, quantum mechanics-polarized ligand docking (QM-PLD) demonstrated good potential to identify larger differences in potencies (predictive index PI = 0.82) and potent inhibitors with K i 's < 10 μM (AU-ROC = 0.86). Accordingly, in silico screening of 2335 new analogues exploiting the ZINC docking database was performed and nine predicted candidates selected for synthesis. The compounds were prepared in O-perbenzoylated forms by either ring transformation of 5-β-d-glucopyranosyl tetrazole by N-benzyl-arenecarboximidoyl chlorides, ring closure of C-(β-d-glucopyranosyl)formamidrazone with aroyl chlorides, or that of N-(β-d-glucopyranosylcarbonyl)arenethiocarboxamides by hydrazine, followed by deprotections. Kinetics experiments against rabbit muscle GPb (rmGPb) and human liver GPa (hlGPa) revealed five compounds as potent low μM inhibitors with three of these on the submicromolar range for rmGPa. X-ray crystallographic analysis sourced the potency to a combination of favorable interactions from the 1,2,4-triazole and suitable aryl substituents in the GP catalytic site. The compounds also revealed promising calculated pharmacokinetic profiles. Copyright © 2018 Elsevier Masson SAS. All rights reserved.
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A data mining method to facilitate SAR transfer.
Wassermann, Anne Mai; Bajorath, Jürgen
2011-08-22
A challenging practical problem in medicinal chemistry is the transfer of SAR information from one chemical series to another. Currently, there are no computational methods available to rationalize or support this process. Herein, we present a data mining approach that enables the identification of alternative analog series with different core structures, corresponding substitution patterns, and comparable potency progression. Scaffolds can be exchanged between these series and new analogs suggested that incorporate preferred R-groups. The methodology can be applied to search for alternative analog series if one series is known or, alternatively, to systematically assess SAR transfer potential in compound databases.
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Cartwright, Steven J
2018-02-01
The use of solvatochromic dyes to investigate homeopathic potencies holds out the promise of understanding the nature of serially succussed and diluted solutions at a fundamental physicochemical level. Recent studies have shown that a range of different dyes interact with potencies and, moreover, the nature of the interaction is beginning to allow certain specific characteristics of potencies to be delineated. The study reported in this article takes previous investigations further and aims to understand more about the nature of the interaction between potencies and solvatochromic dyes. To this end, the UV-visible spectra of a wide range of potential detectors of potencies have been examined using methodologies previously described. Results presented demonstrate that solvatochromic dyes are a sub-group of a larger class of compounds capable of demonstrating interactions with potencies. In particular, amino acids containing an aromatic bridge also show marked optical changes in the presence of potencies. Several specific features of molecular detectors can now be shown to be necessary for significant interactions with homeopathic potencies. These include systems with a large dipole moment, electron delocalisation, polarizability and molecular rigidity. Analysis of the optical changes occurring on interaction with potencies suggests that in all cases potencies increase the polarity of molecular detectors to a degree that correlates with the size of the compound's permanent or ground dipole moment. These results can be explained by inferring that potencies themselves have polarity. Possible candidates for the identity of potencies, based on these and previously reported results, are discussed. The Faculty of Homeopathy.
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Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk.
Maxwell, G L; Schildkraut, J M; Calingaert, B; Risinger, J I; Dainty, L; Marchbanks, P A; Berchuck, A; Barrett, J C; Rodriguez, G C
2006-11-01
Using data from a case-control study of endometrial cancer, we investigated the relationship between the progestin and estrogen potency in combination oral contraceptives (OCs) and the risk of developing endometrial cancer. Subjects included 434 endometrial cancer cases and 2,557 controls identified from the Cancer and Steroid Hormone (CASH) study. OCs were classified into four categories according to the individual potencies of each hormonal constituent (high versus low estrogen or progestin potency). Logistic regression was used to evaluate associations between endometrial cancer risk and combination OC formulations. With non-users as the referent group, use of OCs with either high potency progestin [odds ratio for endometrial cancer (OR)=0.21, 95% confidence interval (CI)=0.10 to 0.43] or with low potency progestin (OR=0.39, 95% CI=0.25 to 0.60) were both associated with a decreased risk of endometrial cancer. Overall high progestin potency OCs did not confer significantly more protection than low progestin potency OCs (OR=0.52, 95% CI=0.24 to 1.14). However, among women with a body mass index of 22.1 kg/m2 or higher, those who used high progestin potency oral contraceptives had a lower risk of endometrial cancer than those who used low progestin potency oral contraceptives (OR=0.31, 95% CI=0.11 to 0.92) while those with a BMI below 22.1 kg/m2 did not (OR=1.36, 95% CI=0.39 to 4.70). The potency of the progestin in most OCs appears adequate to provide a protective effect against endometrial cancer. Higher progestin-potency OCs may be more protective than lower progestin potency OCs among women with a larger body habitus.
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Roberts, David W; Api, Anne Marie
2018-07-01
Prediction of skin sensitisation potential and potency by non-animal methods is the target of many active research programmes. Although the aim is to predict sensitisation potential and potency in humans, data from the murine local lymph node assay (LLNA) constitute much the largest source of quantitative data on in vivo skin sensitisation. The LLNA has been the preferred in vivo method for identification of skin sensitising chemicals and as such is potentially valuable as a benchmark for assessment of non-animal approaches. However, in common with all predictive test methods, the LLNA is subject to false positives and false negatives with an overall level of accuracy said variously to be approximately 80% or 90%. It is also necessary to consider the extent to which, for true positives, LLNA potency correlates with human potency. In this paper LLNA potency and human potency are compared so as to express quantitatively the correlation between them, and reasons for non-agreement between LLNA and human potency are analysed. This leads to a better definition of the applicability domain of the LLNA, within which LLNA data can be used confidently to predict human potency and as a benchmark to assess the performance of non-animal approaches. Copyright © 2018. Published by Elsevier Inc.
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Characterization of the biological activity of a potent small molecule Hec1 inhibitor TAI-1
2014-01-01
Background Hec1 (NDC80) is an integral part of the kinetochore and is overexpressed in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. A highly potent first-in-class compound targeting Hec1, TAI-1, was identified and is characterized in this study to determine its potential as an anticancer agent for clinical utility. Methods The in vitro potency, cancer cell specificity, synergy activity, and markers for response of TAI-1 were evaluated with cell lines. Mechanism of action was confirmed with western blotting and immunofluorescent staining. The in vivo potency of TAI-1 was evaluated in three xenograft models in mice. Preliminary toxicity was evaluated in mice. Specificity to the target was tested with a kinase panel. Cardiac safety was evaluated with hERG assay. Clinical correlation was performed with human gene database. Results TAI-1 showed strong potency across a broad spectrum of tumor cells. TAI-1 disrupted Hec1-Nek2 protein interaction, led to Nek2 degradation, induced significant chromosomal misalignment in metaphase, and induced apoptotic cell death. TAI-1 was effective orally in in vivo animal models of triple negative breast cancer, colon cancer and liver cancer. Preliminary toxicity shows no effect on the body weights, organ weights, and blood indices at efficacious doses. TAI-1 shows high specificity to cancer cells and to target and had no effect on the cardiac channel hERG. TAI-1 is synergistic with doxorubicin, topotecan and paclitaxel in leukemia, breast and liver cancer cells. Sensitivity to TAI-1 was associated with the status of RB and P53 gene. Knockdown of RB and P53 in cancer cells increased sensitivity to TAI-1. Hec1-overexpressing molecular subtypes of human lung cancer were identified. Conclusions The excellent potency, safety and synergistic profiles of this potent first-in-class Hec1-targeted small molecule TAI-1 show its potential for clinically utility in anti-cancer treatment regimens. PMID:24401611
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Bravery, Christopher A; Carmen, Jessica; Fong, Timothy; Oprea, Wanda; Hoogendoorn, Karin H; Woda, Juliana; Burger, Scott R; Rowley, Jon A; Bonyhadi, Mark L; Van't Hof, Wouter
2013-01-01
The evaluation of potency plays a key role in defining the quality of cellular therapy products (CTPs). Potency can be defined as a quantitative measure of relevant biologic function based on the attributes that are linked to relevant biologic properties. To achieve an adequate assessment of CTP potency, appropriate in vitro or in vivo laboratory assays and properly controlled clinical data need to be created. The primary objective of a potency assay is to provide a mechanism by which the manufacturing process and the final product for batch release are scrutinized for quality, consistency and stability. A potency assay also provides the basis for comparability assessment after process changes, such as scale-up, site transfer and new starting materials (e.g., a new donor). Potency assays should be in place for early clinical development, and validated assays are required for pivotal clinical trials. Potency is based on the individual characteristics of each individual CTP, and the adequacy of potency assays will be evaluated on a case-by-case basis by regulatory agencies. We provide an overview of the expectations and challenges in development of potency assays specific for CTPs; several real-life experiences from the cellular therapy industry are presented as illustrations. The key observation and message is that aggressive early investment in a solid potency evaluation strategy can greatly enhance eventual CTP deployment because it can mitigate the risk of costly product failure in late-stage development. Copyright © 2013. Published by Elsevier Inc.
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Development of Special Biological Products
1981-01-01
Rocky Mountain Spotted Fever (RMSF) 20. Continued B. Tissue Culture / ?Two production lots of FRhL-2 dnd three of MRC-5 were stabilized...104) was potency tested. J. Q Fever Vaccine Storage Stability Potency Testing Q fever vaccine (NDBR 105) was put on potency test. K. Rocky Mountain Spotted Fever (RMSF...Fever Vaccine Storage Stability Potency Testing Two lots of Q fever vaccine (NDBR 105) were put on potency test. K. Rocky Mountain Spotted Fever
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Bošnjaković-Pavlović, Nada; Bajuk-Bogdanović, Danica; Zakrzewska, Joanna; Yan, Zeyin; Holclajtner-Antunović, Ivanka; Gillet, Jean-Michel; Spasojević-de Biré, Anne
2017-11-01
Influence of 12-tungstophosphoric acid (WPA) on conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) in the presence of Na + /K + -ATPase was monitored by 31 P NMR spectroscopy. It was shown that WPA exhibits inhibitory effect on Na + /K + -ATPase activity. In order to study WPA reactivity and intermolecular interactions between WPA oxygen atoms and different proton donor types (D=O, N, C), we have considered data for WPA based compounds from the Cambridge Structural Database (CSD), the Crystallographic Open Database (COD) and the Inorganic Crystal Structure Database (ICSD). Binding properties of Keggin's anion in biological systems are illustrated using Protein Data Bank (PDB). This work constitutes the first determination of theoretical Bader charges on polyoxotungstate compound via the Atom In Molecule theory. An analysis of electrostatic potential maps at the molecular surface and charge of WPA, resulting from DFT calculations, suggests that the preferred protonation site corresponds to WPA bridging oxygen. These results enlightened WPA chemical reactivity and its potential biological applications such as the inhibition of the ATPase activity. Copyright © 2017 Elsevier Inc. All rights reserved.
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Potentially biogenic carbon preserved in a 4.1 billion-year-old zircon.
Bell, Elizabeth A; Boehnke, Patrick; Harrison, T Mark; Mao, Wendy L
2015-11-24
Evidence of life on Earth is manifestly preserved in the rock record. However, the microfossil record only extends to ∼ 3.5 billion years (Ga), the chemofossil record arguably to ∼ 3.8 Ga, and the rock record to 4.0 Ga. Detrital zircons from Jack Hills, Western Australia range in age up to nearly 4.4 Ga. From a population of over 10,000 Jack Hills zircons, we identified one >3.8-Ga zircon that contains primary graphite inclusions. Here, we report carbon isotopic measurements on these inclusions in a concordant, 4.10 ± 0.01-Ga zircon. We interpret these inclusions as primary due to their enclosure in a crack-free host as shown by transmission X-ray microscopy and their crystal habit. Their δ(13)CPDB of -24 ± 5‰ is consistent with a biogenic origin and may be evidence that a terrestrial biosphere had emerged by 4.1 Ga, or ∼ 300 My earlier than has been previously proposed.
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Potentially biogenic carbon preserved in a 4.1 billion-year-old zircon
Bell, Elizabeth A.; Harrison, T. Mark; Mao, Wendy L.
2015-01-01
Evidence of life on Earth is manifestly preserved in the rock record. However, the microfossil record only extends to ∼3.5 billion years (Ga), the chemofossil record arguably to ∼3.8 Ga, and the rock record to 4.0 Ga. Detrital zircons from Jack Hills, Western Australia range in age up to nearly 4.4 Ga. From a population of over 10,000 Jack Hills zircons, we identified one >3.8-Ga zircon that contains primary graphite inclusions. Here, we report carbon isotopic measurements on these inclusions in a concordant, 4.10 ± 0.01-Ga zircon. We interpret these inclusions as primary due to their enclosure in a crack-free host as shown by transmission X-ray microscopy and their crystal habit. Their δ13CPDB of −24 ± 5‰ is consistent with a biogenic origin and may be evidence that a terrestrial biosphere had emerged by 4.1 Ga, or ∼300 My earlier than has been previously proposed. PMID:26483481
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Emotional connotations of words related to authority and community.
Schauenburg, Gesche; Ambrasat, Jens; Schröder, Tobias; von Scheve, Christian; Conrad, Markus
2015-09-01
We present a database of 858 German words from the semantic fields of authority and community, which represent core dimensions of human sociality. The words were selected on the basis of co-occurrence profiles of representative keywords for these semantic fields. All words were rated along five dimensions, each measured by a bipolar semantic-differential scale: Besides the classic dimensions of affective meaning (valence, arousal, and potency), we collected ratings of authority and community with newly developed scales. The results from cluster, correlational, and multiple regression analyses on the rating data suggest a robust negativity bias for authority valuation among German raters recruited via university mailing lists, whereas community ratings appear to be rather unrelated to the well-established affective dimensions. Furthermore, our data involve a strong overall negative correlation-rather than the classical U-shaped distribution-between valence and arousal for socially relevant concepts. Our database provides a valuable resource for research questions at the intersection of cognitive neuroscience and social psychology. It can be downloaded as supplemental materials with this article.
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9 CFR 113.9 - New potency test.
Code of Federal Regulations, 2010 CFR
2010-01-01
... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false New potency test. 113.9 Section 113.9 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES... New potency test. A potency test written into the filed Outline of Production for a product shall be...
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Vasoconstriction Potency Induced by Aminoamide Local Anesthetics Correlates with Lipid Solubility
Sung, Hui-Jin; Ok, Seong-Ho; Sohn, Jin-Young; Son, Yong Hyeok; Kim, Jun Kyu; Lee, Soo Hee; Han, Jeong Yeol; Lim, Dong Hoon; Shin, Il-Woo; Lee, Heon-Keun; Chung, Young-Kyun; Choi, Mun-Jeoung; Sohn, Ju-Tae
2012-01-01
Aminoamide local anesthetics induce vasoconstriction in vivo and in vitro. The goals of this in vitro study were to investigate the potency of local anesthetic-induced vasoconstriction and to identify the physicochemical property (octanol/buffer partition coefficient, pKa, molecular weight, or potency) of local anesthetics that determines their potency in inducing isolated rat aortic ring contraction. Cumulative concentration-response curves to local anesthetics (levobupivacaine, ropivacaine, lidocaine, and mepivacaine) were obtained from isolated rat aorta. Regression analyses were performed to determine the relationship between the reported physicochemical properties of local anesthetics and the local anesthetic concentration that produced 50% (ED50) of the local anesthetic-induced maximum vasoconstriction. We determined the order of potency (ED50) of vasoconstriction among local anesthetics to be levobupivacaine > ropivacaine > lidocaine > mepivacaine. The relative importance of the independent variables that affect the vasoconstriction potency is octanol/buffer partition coefficient > potency > pKa > molecular weight. The ED50 in endothelium-denuded aorta negatively correlated with the octanol/buffer partition coefficient of local anesthetics (r2 = 0.9563; P < 0.001). The potency of the vasoconstriction in the endothelium-denuded aorta induced by local anesthetics is determined primarily by lipid solubility and, in part, by other physicochemical properties including potency and pKa. PMID:22778542
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Effect of high-potency cannabis on corpus callosum microstructure.
Rigucci, S; Marques, T R; Di Forti, M; Taylor, H; Dell'Acqua, F; Mondelli, V; Bonaccorso, S; Simmons, A; David, A S; Girardi, P; Pariante, C M; Murray, R M; Dazzan, P
2016-03-01
The use of cannabis with higher Δ9-tetrahydrocannabinol content has been associated with greater risk, and earlier onset, of psychosis. However, the effect of cannabis potency on brain morphology has never been explored. Here, we investigated whether cannabis potency and pattern of use are associated with changes in corpus callosum (CC) microstructural organization, in patients with first-episode psychosis (FEP) and individuals without psychosis, cannabis users and non-users. The CC of 56 FEP (37 cannabis users) and 43 individuals without psychosis (22 cannabis users) was virtually dissected and segmented using diffusion tensor imaging tractography. The diffusion index of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity was calculated for each segment. Across the whole sample, users of high-potency cannabis had higher total CC MD and higher total CC AD than both low-potency users and those who never used (p = 0.005 and p = 0.004, respectively). Daily users also had higher total CC MD and higher total CC AD than both occasional users and those who never used (p = 0.001 and p < 0.001, respectively). However, there was no effect of group (patient/individuals without psychosis) or group x potency interaction for either potency or frequency of use. The within-group analysis showed in fact that the effects of potency and frequency were similar in FEP users and in users without psychosis. Frequent use of high-potency cannabis is associated with disturbed callosal microstructural organization in individuals with and without psychosis. Since high-potency preparations are now replacing traditional herbal drugs in many European countries, raising awareness about the risks of high-potency cannabis is crucial.
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Whaley, J. Taylor; Levy, Lawrence B.; Swanson, David A.; Pugh, Thomas J.; Kudchadker, Rajat J.; Bruno, Teresa L.; Frank, Steven J.
2013-01-01
Purpose Prospective evaluation of sexual outcomes after prostate brachytherapy with iodine-125 seeds as monotherapy at a tertiary cancer care center. Methods and Materials Subjects were 129 men with prostate cancer with I-125 seed implants (prescribed dose, 145 Gy) without supplemental hormonal or external beam radiation therapy. Sexual function, potency, and bother were prospectively assessed at baseline and at 1, 4, 8, and 12 months using validated quality-of-life self-assessment surveys. Postimplant dosimetry values, including dose to 10% of the penile bulb (D10), D20, D33, D50, D75, D90, and penile-volume receiving 100% of the prescribed dose (V100) were calculated. Results At baseline, 56% of patients recorded having optimal erections; at 1 year, 62% of patients with baseline erectile function maintained optimal potency, 58% of whom with medically prescribed sexual aids or drugs. Variables associated with pretreatment-to-posttreatment decline in potency were time after implant (p=0.04) and age (p=0.01). Decline in urinary function may have been related to decline in potency. At 1 year, 69% of potent patients younger than 70 years maintained optimal potency, whereas 31% of patients over 70 maintained optimal potency (p=0.02). Diabetes was related to a decline in potency (p=0.05), but neither smoking nor hypertension were. For patients with optimal potency at baseline, mean sexual bother scores had declined significantly at 1 year (p<0.01). Sexual potency, sexual function, and sexual bother scores failed to correlate with any dosimetric variable tested. Conclusions Erections firm enough for intercourse can be achieved at 1 year after treatment, but most men will require medical aids to optimize potency. Although younger men were better able to maintain erections firm enough for intercourse than older men, there was no correlation between potency, sexual function, or sexual bother and penile bulb dosimetry. PMID:22300559
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Whaley, J Taylor; Levy, Lawrence B; Swanson, David A; Pugh, Thomas J; Kudchadker, Rajat J; Bruno, Teresa L; Frank, Steven J
2012-04-01
Prospective evaluation of sexual outcomes after prostate brachytherapy with iodine-125 seeds as monotherapy at a tertiary cancer care center. Subjects were 129 men with prostate cancer with I-125 seed implants (prescribed dose, 145 Gy) without supplemental hormonal or external beam radiation therapy. Sexual function, potency, and bother were prospectively assessed at baseline and at 1, 4, 8, and 12 months using validated quality-of-life self-assessment surveys. Postimplant dosimetry values, including dose to 10% of the penile bulb (D10), D20, D33, D50, D75, D90, and penile volume receiving 100% of the prescribed dose (V100) were calculated. At baseline, 56% of patients recorded having optimal erections; at 1 year, 62% of patients with baseline erectile function maintained optimal potency, 58% of whom with medically prescribed sexual aids or drugs. Variables associated with pretreatment-to-posttreatment decline in potency were time after implant (p = 0.04) and age (p = 0.01). Decline in urinary function may have been related to decline in potency. At 1 year, 69% of potent patients younger than 70 years maintained optimal potency, whereas 31% of patients older than 70 maintained optimal potency (p = 0.02). Diabetes was related to a decline in potency (p = 0.05), but neither smoking nor hypertension were. For patients with optimal potency at baseline, mean sexual bother scores had declined significantly at 1 year (p < 0.01). Sexual potency, sexual function, and sexual bother scores failed to correlate with any dosimetric variable tested. Erections firm enough for intercourse can be achieved at 1 year after treatment, but most men will require medical aids to optimize potency. Although younger men were better able to maintain erections firm enough for intercourse than older men, there was no correlation between potency, sexual function, or sexual bother and penile bulb dosimetry. Copyright © 2012 Elsevier Inc. All rights reserved.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Whaley, J. Taylor; Levy, Lawrence B.; Swanson, David A.
Purpose: Prospective evaluation of sexual outcomes after prostate brachytherapy with iodine-125 seeds as monotherapy at a tertiary cancer care center. Methods and Materials: Subjects were 129 men with prostate cancer with I-125 seed implants (prescribed dose, 145 Gy) without supplemental hormonal or external beam radiation therapy. Sexual function, potency, and bother were prospectively assessed at baseline and at 1, 4, 8, and 12 months using validated quality-of-life self-assessment surveys. Postimplant dosimetry values, including dose to 10% of the penile bulb (D10), D20, D33, D50, D75, D90, and penile volume receiving 100% of the prescribed dose (V100) were calculated. Results: Atmore » baseline, 56% of patients recorded having optimal erections; at 1 year, 62% of patients with baseline erectile function maintained optimal potency, 58% of whom with medically prescribed sexual aids or drugs. Variables associated with pretreatment-to-posttreatment decline in potency were time after implant (p = 0.04) and age (p = 0.01). Decline in urinary function may have been related to decline in potency. At 1 year, 69% of potent patients younger than 70 years maintained optimal potency, whereas 31% of patients older than 70 maintained optimal potency (p = 0.02). Diabetes was related to a decline in potency (p = 0.05), but neither smoking nor hypertension were. For patients with optimal potency at baseline, mean sexual bother scores had declined significantly at 1 year (p < 0.01). Sexual potency, sexual function, and sexual bother scores failed to correlate with any dosimetric variable tested. Conclusions: Erections firm enough for intercourse can be achieved at 1 year after treatment, but most men will require medical aids to optimize potency. Although younger men were better able to maintain erections firm enough for intercourse than older men, there was no correlation between potency, sexual function, or sexual bother and penile bulb dosimetry.« less
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Growth and development of spring towers at Shiqiang, Yunnan Province, China
NASA Astrophysics Data System (ADS)
Jones, Brian; Peng, Xiaotong
2017-01-01
Throughout the world, high artesian pressures in hydrothermal areas have led to the growth of tall spring towers that have their vents at their summits. The factors that control their development and formative precipitates are poorly understood because these springs, irrespective of location, are mostly inactive. Spring towers found at Shiqiang (Yunnan Province, China), which are up to 4 m high and 3 m in diameter, are formed largely of calcite and aragonite crystal bushes, euhedral calcite crystals and coated grains with alternating Fe-poor and Fe-rich zones, calcite rafts, and cements formed of various combinations of calcite, aragonite, strontianite, Mg-Si reticulate, needle fiber calcite, calcified and non-calcified microbes, diatoms, and insects. Collectively, the limestones that form the towers can be divided into (1) Group A that are friable, porous and form the cores of the towers and have δ18OSMOW values of + 15.7 to + 19.7‰ (average 17.8‰) and δ13CPDB values of + 5.1 to + 6.9‰ (average 5.9‰), and (2) Group B that are hard and well lithified and found largely around the vents and the tower sides, and have δ18OSMOW values of + 13.0 to + 22.0‰ (average 17.6‰) and δ13CPDB values of + 1.4 to + 3.6‰ (average 2.6‰). The precipitates and the isotopic values indicate that these were thermogene springs. Growth of the Shiqiang spring towers involved (1) Phase IA when precipitation of calcite and aragonite bushes formed the core of the tower and Phase IB when calcite, commonly Fe-rich, was precipitated locally, (2) Phase II that involved the precipitation of white cements, formed of calcite, aragonite, strontianite, and Mg-Si reticulate coatings in cavities amid the Phase I precipitates, and (3) Phase III, which formed probably after spring activity ceased, when needle-fiber calcite was precipitated and the mounds were invaded by microbes (some now calcified), diatoms, and insects. At various times during this complex history, pore waters mediated dissolution of the calcite and aragonite and sometimes partial alteration of the aragonite. The diverse array of precipitates, depositional fabrics and diagenetic changes clearly indicate that the composition of the spring water changed frequently. Growth of the spring towers at Shiqiang continued until there was insufficient artesian pressure to lift the water above the top of the tower vent.
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NASA Astrophysics Data System (ADS)
Kuleshova, L. N.; Hofmann, D. W. M.; Boese, R.
2013-03-01
Cocrystals (or multicomponent crystals) have physico-chemical properties that are different from crystals of pure components. This is significant in drug development, since the desired properties, e.g. solubility, stability and bioavailability, can be tailored by binding two substances into a single crystal without chemical modification of an active component. Here, the FLEXCRYST program suite, implemented with a data mining force field, was used to estimate the relative stability and, consequently, the relative solubility of cocrystals of flavonoids vs their pure crystals, stored in the Cambridge Structural Database. The considerable potency of this approach for in silico screening of cocrystals, as well as their relative solubility, was demonstrated.
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Potency control of modified live viral vaccines for veterinary use.
Terpstra, C; Kroese, A H
1996-04-01
This paper reviews various aspects of efficacy, and methods for assaying the potency of modified live viral vaccines. The pros and cons of parametric versus non-parametric methods for analysis of potency assays are discussed and critical levels of protection, as determined by the target(s) of vaccination, are exemplified. Recommendations are presented for designing potency assays on master virus seeds and vaccine batches.
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Potency control of modified live viral vaccines for veterinary use.
Terpstra, C; Kroese, A H
1996-01-01
This paper reviews various aspects of efficacy, and methods for assaying the potency of modified live viral vaccines. The pros and cons of parametric versus non-parametric methods for analysis of potency assays are discussed and critical levels of protection, as determined by the target(s) of vaccination, are exemplified. Recommendations are presented for designing potency assays on master virus seeds and vaccine batches.
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Eichelberger, Schafer L; Sultana, Ishrat; Gao, Jin; Getie-Kebtie, Melkamu; Alterman, Michail; Eichelberger, Maryna C
2013-11-01
Influenza vaccines are effective in protecting against illness and death caused by this seasonal pathogen. The potency of influenza vaccines is measured by single radial immunodiffusion (SRID) assay that quantifies antigenic forms of hemagglutinin (HA). Hydrostatic pressure results in loss of binding of influenza virus to red blood cells, but it is not known whether this infers loss of potency. Our goal was to determine the impact of pressure on HA antigenic structure. Viruses included in the 2010-2011 trivalent influenza vaccine were subjected to increasing number of cycles at 35,000 psi in a barocycler, and the impact of this treatment measured by determining hemagglutination units (HAU) and potency. Potency was assessed by SRID and immunogenicity in mice. After 25 cycles of pressure, the potency measured by SRID assay was below the limit of quantification for the H1N1 and B viruses used in our study, while the H3N2 component retained some potency that was lost after 50 pressure cycles. Pressure treatment also resulted in loss of HAU, but this did not strictly correlate with the potency value. Curiously, loss of potency was abrogated when influenza A, but not B, antigens were exposed to pressure in chicken egg allantoic fluid. Protection against pressure appeared to be mediated by specific interactions because addition of bovine serum albumin did not have the same effect. Our results show that pressure-induced loss of potency is strain dependent and suggests that pressure treatment may be useful for identifying vaccine formulations that improve HA stability. Published 2013. This article is U.S. Government work and in the public domain in the USA.
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Asselmann, Eva; Wittchen, Hans-Ulrich; Lieb, Roselind; Beesdo-Baum, Katja
2015-04-01
This study aims to examine whether (a) low child valence (emotional connectedness) within the mother-child relationship increases the risk for offspring depression, (b) low child potency (individual autonomy) increases the risk for offspring anxiety, and (c) maternal psychopathology pronounces these associations. We used data from a prospective-longitudinal study of adolescents (aged 14-17 at baseline) and their mothers (N = 1,015 mother-child dyads). Anxiety disorders and depression were assessed repeatedly over 10 years in adolescents (T0, T1, T2, T3) and their mothers (T1, T3) using the DSM-IV/M-CIDI. Valence and potency were assessed in mothers (T1) with the Subjective Family Image Questionnaire. Odds ratios (OR) from logistic regression were used to estimate associations between low child valence/potency and offspring psychopathology (cumulated lifetime incidences; adjusted for sex and age). In separate models (low valence or low potency as predictor), low child valence predicted offspring depression only (OR = 1.26 per SD), while low child potency predicted offspring anxiety (OR = 1.24) and depression (OR = 1.24). In multiple models (low valence and low potency as predictors), low child valence predicted offspring depression only (OR = 1.19), while low child potency predicted offspring anxiety only (OR = 1.22). Low child potency interacted with maternal anxiety on predicting offspring depression (OR = 1.49), i.e. low child potency predicted offspring depression only in the presence of maternal anxiety (OR = 1.33). These findings suggest that low child valence increases the risk for offspring depression, while low child potency increases the risk for offspring anxiety and depression and interacts with maternal psychopathology on predicting offspring depression.
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Freeman, T P; Winstock, A R
2015-11-01
Cannabis use is decreasing in England and Wales, while demand for cannabis treatment in addiction services continues to rise. This could be partly due to an increased availability of high-potency cannabis. Adults residing in the UK were questioned about their drug use, including three types of cannabis (high potency: skunk; low potency: other grass, resin). Cannabis types were profiled and examined for possible associations between frequency of use and (i) cannabis dependence, (ii) cannabis-related concerns. Frequent use of high-potency cannabis predicted a greater severity of dependence [days of skunk use per month: b = 0.254, 95% confidence interval (CI) 0.161-0.357, p < 0.001] and this effect became stronger as age decreased (b = -0.006, 95% CI -0.010 to -0.002, p = 0.004). By contrast, use of low-potency cannabis was not associated with dependence (days of other grass use per month: b = 0.020, 95% CI -0.029 to 0.070, p = 0.436; days of resin use per month: b = 0.025, 95% CI -0.019 to 0.067, p = 0.245). Frequency of cannabis use (all types) did not predict severity of cannabis-related concerns. High-potency cannabis was clearly distinct from low-potency varieties by its marked effects on memory and paranoia. It also produced the best high, was preferred, and most available. High-potency cannabis use is associated with an increased severity of dependence, especially in young people. Its profile is strongly defined by negative effects (memory, paranoia), but also positive characteristics (best high, preferred type), which may be important when considering clinical or public health interventions focusing on cannabis potency.
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Good, M; Clegg, T A; Costello, E; More, S J
2011-11-01
In national bovine tuberculosis (BTB) control programmes, testing is generally conducted using a single source of bovine purified protein derivative (PPD) tuberculin. Alternative tuberculin sources should be identified as part of a broad risk management strategy as problems of supply or quality cannot be discounted. This study was conducted to compare the impact of different potencies of a single bovine PPD tuberculin on the field performance of the single intradermal comparative tuberculin test (SICTT) and single intradermal test (SIT). Three trial potencies of bovine PPD tuberculin, as assayed in naturally infected bovines, namely, low (1192IU/dose), normal (6184IU/dose) and high (12,554IU/dose) were used. Three SICTTs (using) were conducted on 2102 animals. Test results were compared based on reactor-status and changes in skin-thickness at the bovine tuberculin injection site. There was a significant difference in the number of reactors detected using the high and low potency tuberculins. In the SICTT, high and low potency tuberculin detected 40% more and 50% fewer reactors, respectively, than normal potency tuberculin. Furthermore, use of the low potency tuberculin in the SICTT failed to detect 20% of 35 animals with visible lesions, and in the SIT 11% of the visible lesion animals would have been classified as negative. Tuberculin potency is critical to the performance of both the SICTT and SIT. Tuberculin of different potencies will affect reactor disclosure rates, confounding between-year or between-country comparisons. Independent checks of tuberculin potency are an important aspect of quality control in national BTB control programmes. Copyright © 2011 Elsevier Ltd. All rights reserved.
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Skrlin, Ana; Kosor Krnic, Ela; Gosak, Darko; Prester, Berislav; Mrsa, Vladimir; Vuletic, Marko; Runac, Domagoj
2010-11-02
In vivo and in vitro potency assays have always been a critical tool for confirmation of protein activity. However, due to their complexity and time consuming procedures, it remains a challenge to find an alternative analytical approach that would enable their replacement with no impact on the quality of provided information. The goal of this research was to determine if a correlation between liquid chromatography assays and in vitro biological assay could be established for filgrastim (recombinant human granulocyte-colony stimulating factor, rhG-CSF) samples containing various amounts of related impurities. For that purpose, relevant filgrastim related impurities were purified to homogeneity and characterized by liquid chromatography and mass spectrometry. A significant correlation (R(2)>0.90) between the two types of assays was revealed. Potency of oxidized filgrastim was determined to be approximately 25% of filgrastim stated potency (1 x 10(8)IU/mg of protein). Formyl-methionine filgrastim had potency of 89% of the filgrastim stated potency, while filgrastim dimer had 67% of filgrastim stated potency. A mathematical model for the estimation of biological activity of filgrastim samples from chromatography data was established and a significant correlation between experimental potency values and potency values estimated by the mathematical model was obtained (R(2)=0.92). Based on these results a conclusion was made that reversed phase high performance liquid chromatography could be used as an alternative for the in vitro biological assay for potency assessment of filgrastim samples. Such an alternative model would enable substitution of a complex and time consuming biological assay with a robust and precise instrumental method in many practical cases. Copyright (c) 2010 Elsevier B.V. All rights reserved.
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Methods for the Quality Control of Inactivated Poliovirus Vaccines.
Wilton, Thomas
2016-01-01
Inactivated poliovirus vaccine (IPV) plays an instrumental role in the Global Poliovirus Eradication Initiative (GPEI). The quality of IPV is controlled by assessment of the potency of vaccine batches. The potency of IPV can be assessed by both in vivo and in vitro methods. In vitro potency assessment is based upon the assessment of the quantity of the D-Antigen (D-Ag) units in an IPV. The D-Ag unit is used as a measure of potency as it is largely expressed on native infectious virions and is the protective immunogen. The most commonly used in vitro test is the indirect ELISA which is used to ensure consistency throughout production.A range of in vivo assays have been developed in monkeys, chicks, guinea pigs, mice, and rats to assess the potency of IPV. All are based on assessment of the neutralizing antibody titer within the sera of the respective animal model. The rat potency test has become the favored in vivo potency test as it shows minimal variation between laboratories and the antibody patterns of rats and humans are similar. With the development of transgenic mice expressing the human poliovirus receptor, immunization-challenge tests have been developed to assess the potency of IPVs. This chapter describes in detail the methodology of these three laboratory tests to assess the quality of IPVs.
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Zheng, Suqing; Santosh Laxmi, Y R; David, Emilie; Dinkova-Kostova, Albena T; Shiavoni, Katherine H; Ren, Yanqing; Zheng, Ying; Trevino, Isaac; Bumeister, Ronald; Ojima, Iwao; Wigley, W Christian; Bliska, James B; Mierke, Dale F; Honda, Tadashi
2012-05-24
Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.
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Schofield, T
2002-01-01
Early in its development, the potency of Merck's recombinant hepatitis B vaccine, RECOMBIVAX HB, was monitored using an assay performed in mice. A specification was determined to be the lowest potency which induced acceptable response in clinical trials. As a post-licensing commitment, Merck was asked to replace its mouse potency assay with an in vitro procedure for product release in the US market. Early studies with a commercial enzyme immunoassay (EIA) yielded highly variable results. That assay, combined with a sample pretreatment step, proved more dependable and predictive of potency in the mouse assay. Based on measurements made on manufactured materials, combined with experiments contrived to yield a wide range of reactivity in the two assays, concordance was established between the EIA and the mouse potency assay. This concordance was used to calibrate a specification for the in vitro assay that is predictive of a satisfactory response in vivo. Data from clinical trials established a correspondence between human immunogenicity and these potency markers.
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An "EAR" on environmental surveillance and monitoring: A ...
Current environmental monitoring approaches focus primarily on chemical occurrence. However, based on chemical concentration alone, it can be difficult to identify which compounds may be of toxicological concern for prioritization for further monitoring or management. This can be problematic because toxicological characterization is lacking for many emerging contaminants. New sources of high throughput screening data like the ToxCast™ database, which contains data for over 9,000 compounds screened through up to 1,100 assays, are now available. Integrated analysis of chemical occurrence data with HTS data offers new opportunities to prioritize chemicals, sites, or biological effects for further investigation based on concentrations detected in the environment linked to relative potencies in pathway-based bioassays. As a case study, chemical occurrence data from a 2012 study in the Great Lakes Basin along with the ToxCast™ effects database were used to calculate exposure-activity ratios (EARs) as a prioritization tool. Technical considerations of data processing and use of the ToxCast™ database are presented and discussed. EAR prioritization identified multiple sites, biological pathways, and chemicals that warrant further investigation. Biological pathways were then linked to adverse outcome pathways to identify potential adverse outcomes and biomarkers for use in subsequent monitoring efforts. Anthropogenic contaminants are frequently reported in environm
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Bioinformatics: Cheap and robust method to explore biomaterial from Indonesia biodiversity
NASA Astrophysics Data System (ADS)
Widodo
2015-02-01
Indonesia has a huge amount of biodiversity, which may contain many biomaterials for pharmaceutical application. These resources potency should be explored to discover new drugs for human wealth. However, the bioactive screening using conventional methods is very expensive and time-consuming. Therefore, we developed a methodology for screening the potential of natural resources based on bioinformatics. The method is developed based on the fact that organisms in the same taxon will have similar genes, metabolism and secondary metabolites product. Then we employ bioinformatics to explore the potency of biomaterial from Indonesia biodiversity by comparing species with the well-known taxon containing the active compound through published paper or chemical database. Then we analyze drug-likeness, bioactivity and the target proteins of the active compound based on their molecular structure. The target protein was examined their interaction with other proteins in the cell to determine action mechanism of the active compounds in the cellular level, as well as to predict its side effects and toxicity. By using this method, we succeeded to screen anti-cancer, immunomodulators and anti-inflammation from Indonesia biodiversity. For example, we found anticancer from marine invertebrate by employing the method. The anti-cancer was explore based on the isolated compounds of marine invertebrate from published article and database, and then identified the protein target, followed by molecular pathway analysis. The data suggested that the active compound of the invertebrate able to kill cancer cell. Further, we collect and extract the active compound from the invertebrate, and then examined the activity on cancer cell (MCF7). The MTT result showed that the methanol extract of marine invertebrate was highly potent in killing MCF7 cells. Therefore, we concluded that bioinformatics is cheap and robust way to explore bioactive from Indonesia biodiversity for source of drug and another pharmaceutical material.
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The pilosebaceous unit—a phthalate-induced pathway to skin sensitization
DOE Office of Scientific and Technical Information (OSTI.GOV)
Simonsson, Carl, E-mail: carl.simonsson@chem.gu.se; Stenfeldt, Anna-Lena; Karlberg, Ann-Therese
2012-10-01
Allergic contact dermatitis (ACD) is caused by low-molecular weight compounds called haptens. It has been shown that the potency of haptens can depend on the formulation in which they are applied on the skin. Specifically the sensitization potency of isothiocyanates, a group of haptens which can be released from e.g. adhesive tapes and neoprene materials, increases with the presence of phthalates; however, the underlying mechanisms are not clear. A better understanding of the mechanisms governing the potency of haptens is important, e.g. to improve the risk assessment and the formulation of chemicals in consumer products. In this study we havemore » explored phthalate-induced effects on the sensitization potency, skin distribution, and reactivity of fluorescent model isothiocyanate haptens using non-invasive two-photon microscopy to provide new insights regarding vehicle effects in ACD. The data presented in this paper indicate that the sensitization potency of isothiocyanates increases when applied in combination with dibutylphthalate due to a specific uptake via the pilosebaceous units. The results highlight the importance of shunt pathways when evaluating the bioavailability of skin sensitizers. The findings also indicate that vehicle-dependent hapten reactivity towards stratum corneum proteins regulates the bioavailability, and thus the potency, of skin sensitizers. -- Highlights: ► Vehicle effects on sensitization potency were investigated in the LLNA. ► In vivo cutaneous absorption of contact sensitizers was visualized using TPM. ► Sensitizing potency of isothiocyanates depends on the presence of a phthalate. ► Phthalate induced cutaneous absorption via the pilosebaceous units. ► Vehicle-dependent reactivity regulates sensitization potency.« less
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The Effects of Medical Marijuana Laws on Potency
Pacula, Rosalie Liccardo; Heaton, Paul
2014-01-01
Background Marijuana potency has risen dramatically over the past two decades. In the United States, it is unclear whether state medical marijuana policies have contributed to this increase. Methods Employing a differences-in-differences model within a mediation framework, we analyzed data on n = 39,157 marijuana samples seized by law enforcement in 51 U.S. jurisdictions between 1990-2010, producing estimates of the direct and indirect effects of state medical marijuana laws on potency, as measured by Δ9-tetrahydrocannabinol content. Results We found evidence that potency increased by a half percentage point on average after legalization of medical marijuana, although this result was not significant. When we examined specific medical marijuana supply provisions, results suggest that legal allowances for retail dispensaries had the strongest influence, significantly increasing potency by about one percentage point on average. Our mediation analyses examining the mechanisms through which medical marijuana laws influence potency found no evidence of direct regulatory impact. Rather, the results suggest that the impact of these laws occurs predominantly through a compositional shift in the share of the market captured by high-potency sinsemilla. Conclusion Our findings have important implications for policymakers and those in the scientific community trying to understand the extent to which greater availability of higher potency marijuana increases the risk of negative public health outcomes, such as drugged driving and drug-induced psychoses. Future work should reconsider the impact of medical marijuana laws on health outcomes in light of dramatic and ongoing shifts in both marijuana potency and the medical marijuana policy environment. PMID:24502887
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Opioid analgesics: does potency matter?
Passik, Steven D; Webster, Lynn
2014-01-01
Prescription opioid analgesics with a wide range of potencies are currently used for the treatment of chronic pain. Yet understanding the clinical relevance and therapeutic consequences of opioid potency remains ill defined. Both patients and clinicians alike have misperceptions about opioid potency, expecting that less-potent opioids will be less effective or fearing that more-potent opioids are more dangerous or more likely to be abused. In this review, common myths about the potency of opioid analgesics will be discussed. Clinicians should understand that pharmacologic potency per se does not necessarily imply more effective analgesia or higher abuse liability. Published dose conversion tables may not accurately calculate the dose for effective and safe rotation from one opioid to another in patients receiving long-term opioid therapy because they are based on limited data that may not apply to chronic pain. Differences in pharmacologic potency are largely accounted for by the actual doses prescribed, according to individualized patient need. Factors for achieving effective analgesia and reducing the risks involved with opioid use include careful medication selection based on patient characteristics, appropriate dosing titration and opioid rotation practices, knowledge of product formulation characteristics (eg, extended release, immediate release, and tamper-resistant features), and an awareness of differences in opioid pharmacokinetics and metabolism. Clinicians should remain vigilant in monitoring patients on any opioid medication, regardless of classification along the opioid potency continuum.
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Using a mass balance to determine the potency loss during the production of a pharmaceutical blend.
Mackaplow, Michael B
2010-09-01
The manufacture of a blend containing the active pharmaceutical ingredient (API) and inert excipients is a precursor for the production of most pharmaceutical capsules and tablets. However, if there is a net water gain or preferential loss of API during production, the potency of the final drug product may be less than the target value. We use a mass balance to predict the mean potency loss during the production of a blend via wet granulation and fluidized bed drying. The result is an explicit analytical equation for the change in blend potency a function of net water gain, solids losses (both regular and high-potency), and the fraction of excipients added extragranularly. This model predicts that each 1% gain in moisture content (as determined by a loss on drying test) will decrease the API concentration of the final blend at least 1% LC. The effect of pre-blend solid losses increases with their degree of superpotency. This work supports Quality by Design by providing a rational method to set the process design space to minimize blend potency losses. When an overage is necessary, the model can help justify it by providing a quantitative, first-principles understanding of the sources of potency loss. The analysis is applicable to other manufacturing processes where the primary sources of potency loss are net water gain and/or mass losses.
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Code of Federal Regulations, 2010 CFR
2010-04-01
... in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in § 600.3(s) of this chapter. ...
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Code of Federal Regulations, 2011 CFR
2011-04-01
... in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in § 600.3(s) of this chapter. ...
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Albert, R E
1983-01-01
Mammalian cell mutagenesis, transformation and skin tumorigenesis assays show similar results in comparing the potencies of diesel, coke oven, roofing tar and cigarette smoke particulates. These assay results are reasonably consistent with the comparative carcinogenic potencies of coke oven and roofing tar emissions as determined by epidemiological studies. The bacterial mutagenesis assay tends to show disproportionately high potencies, particularly with diesel particulates. Results to date encourage the approach to the assessment for carcinogenic risks from diesel emissions based on the use of epidemiological data on cancer induced by coke oven emissions, roofing tar particulates and cigarette smoke with the comparative potencies of these materials determined by in vivo and in vitro bioassays. PMID:6186481
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Potency Determination of Antidandruff Shampoos in Nystatin International Unit Equivalents
Anusha Hewage, D. B. G.; Pathirana, W.; Pinnawela, Amara
2008-01-01
A convenient standard microbiological potency determination test for the antidandruff shampoos was developed by adopting the pharmacopoeial microbiological assay procedure of the drug nystatin. A standard curve was drawn consisting of the inhibition zone diameters vs. logarithm of nystatin concentrations in international units using the fungus Saccharomyces cerevisiae (yeast) strain National Collection of Type Culture (NCTC) 1071606 as the test organism. From the standard curve the yeast inhibitory potencies of the shampoos in nystatin international unit equivalents were determined from the respective inhibition zones of the test samples of the shampoos. Under test conditions four shampoo samples showed remarkable fungal inhibitory potencies of 10227, 10731, 12396 and 18211 nystatin international unit equivalents/ml while two shampoo samples had extremely feeble inhibitory potencies 4.07 and 4.37 nystatin international unit equivalents/ml although the latter two products claimed antifungal activity. The potency determination method could be applied to any antidandruff shampoo with any one or a combination of active ingredients. PMID:21394271
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Dressler, Dirk; Mander, Gerd; Fink, Klaus
2012-01-01
The biological potency of botulinum toxin (BT) drugs is determined by a standardised LD50 assay. However, the potency labelling varies vary amongst different BT drugs. One reason for this may be differences in the LD50 assays applied. When five unexpired batches of onabotulinumtoxinA (Botox(®)) and incobotulinumtoxinA (Xeomin(®)) are compared in the Xeomin(®) batch release assay, the potency variability of both BT drugs fell within the range allowed by the European Pharmacopoiea. Statistical analyses failed to detect differences in the potency labelling of both products. Although the existence of a conversion ratio has been questioned recently, our experimental data are in line with previous clinical experience showing that Botox(®) and Xeomin(®) can be compared using a 1:1 conversion ratio. Identical potency labelling allows easy exchange of both BT drugs in a therapeutic setting, and direct comparison of efficacy, adverse effects and costs.
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Weng, Hong; Zeng, Xian-Tao; Li, Sheng; Meng, Xiang-Yu; Shi, Ming-Jun; He, Da-Lin; Wang, Xing-Huan
2017-09-13
The present study aimed to systematically evaluate the effectiveness and safety of the intrafascial and interfascial nerve sparing (ITR-NS and ITE-NS) radical prostatectomy. PubMed, Embase, and Cochrane Library databases were searched for eligible studies. Meta-analysis with random-effects model was performed. Six comparative trials were selected and embraced in this research, including one randomized controlled trial, three prospective comparative trials, and two retrospective comparative trials. With regard to perioperative parameters, no significant association of operative time, blood loss, transfusion rates, duration of catheterization, and hospital stay existed between ITR-NS and ITE-NS. With respect to the functional results, ITR-NS had advantages in terms of both continence and potency recovery compared with ITE-NS. In reference to the oncologic results, the ITR-NS showed lower overall positive surgical margin (PSM) compared with ITE-NS but pT2 PSM and biochemical recurrence free rates were similar to the two surgical types. This study demonstrates that ITR-NS has better continence at 6 mo and 36 mo and better potency recovery at 6 mo and 12 mo postoperatively, regardless of the surgical technique. The cancer control of ITR-NS was also better than that of ITE-NS. This may be explained by the fact that patients in ITE-NS group present higher risk cancer than patients in ITR-NS group.
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NASA Astrophysics Data System (ADS)
Peoples, Robert W.; Weight, Forrest F.
1995-03-01
As the number of carbon atoms in an aliphatic n-alcohol is increased from one to five, intoxicating potency, lipid solubility, and membrane lipid disordering potency all increase in a similar exponential manner. However, the potency of aliphatic n-alcohols for producing intoxication reaches a maximum at six to eight carbon atoms and then decreases. The molecular basis of this "cutoff" effect is not understood, as it is not correlated with either the lipid solubility or the membrane disordering potency of the alcohols, which continue to increase exponentially. Since it has been suggested that inhibition of N-methyl-D-aspartate (NMDA) receptors by alcohols may play a role in alcohol intoxication, we investigated whether a series of aliphatic n-alcohols would exhibit a cutoff in potency for inhibition of NMDA receptors. We found that although potency for inhibition of NMDA receptors increased exponentially for alcohols with one to five carbon atoms, potency for inhibition of NMDA receptors reached a maximum at six to eight carbon atoms and then abruptly disappeared. This cutoff for alcohol inhibition of NMDA receptors is consistent with an interaction of the alcohols with a hydrophobic pocket on the receptor protein. In addition, the similarity of the cutoffs for alcohol inhibition of NMDA receptors and alcohol intoxication suggests that the cutoff for NMDA receptor inhibition may contribute to the cutoff for alcohol intoxication, which is consistent with an important role of NMDA receptors in alcohol intoxication.
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NASA Astrophysics Data System (ADS)
Zhu, Shifa; Qin, Yi; Liu, Xin; Wei, Chengjie; Zhu, Xiaomin; Zhang, Wei
2017-04-01
Although dolomitization of calcite minerals and carbonatization of volcanic rocks have been studied widely, the extensive dolomitic rocks that originated from altered volcanic and volcaniclastic rocks have not been reported. The dolomitic rocks of the Fengcheng Formation in the Junggar Basin of China appear to be formed under unusual geologic conditions. The petrological and geochemical characteristics indicate that the dolomitizing host rock is devitrified volcanic tuff. After low-temperature alteration and calcitization, these tuffaceous rocks are replaced by Mg-rich brine to form massive dolomitic tuffs. We propose that the briny (with -2 ‰ 6 ‰ of δ13CPDB and -5 ‰ 4 ‰ of δ18OPDB) and Mg-rich marine formation water (with 0.7060 0.7087 of 87Sr/86Sr ratio), the thick and intermediate-mafic volcanic ashes, and the tectonically compressional movement may have favored the formation of the unusual dolomitic rocks. We conclude that the proposed origin of the dolomitic rocks can be extrapolated to other similar terranes with volcaniclastic rocks, seabed tuffaceous sediment, and fracture filling of sill.
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NASA Astrophysics Data System (ADS)
Matson, Ernest A.
1989-01-01
Stable C isotope ratios (δ13C-PDB), percentages of organic matter, and HCl insoluble ash and soluble carbonates, extractable Fe, Al, Si and P were used to determine the distribution and accumulation of terrestrial material in reef-flat moats and lagoons of two high islands (Guam and Saipan) in the western tropical Pacific. Carbonate sediments of a reef-flat moat infiltrated by seepage of aquifer waters (but without surface runoff) were depleted in both P (by 38%) and 13C (by 41%) and enriched in Si (by 100%) relative to offshore lagoon sediments. Iron and ash accumulated in depositional regimes regardless of the occurrence of runoff but was depleted from coarse-grained carbonates in turbulent regimes. Aluminum (>ca. 10 to 20 μmol g-1), Fe (>ca. 1 to 3 μmol g-1) and ash (>0.5%) indicated terrigenous influence which was corroborated by depletions in both 13C and P. Low-salinity geochemical segregation, natural biochemical accumulation, as well as long-shore currents and eddies help sequester these materials nearshore.
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RELATIVE POTENCY OF FUNGAL EXTRACTS IN INDUCING ALLERGIC ASTHMA-LIKE RESPONSES IN BALB/C MICE
Indoor mold has been associated with the development of allergic asthma. However, relative potency of molds in the induction of allergic asthma is not clear. In this study, we tested the relative potency of fungal extracts (Metarizium anisophilae [MACA], Stachybotrys ...
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9 CFR 114.9 - Outline of Production guidelines.
Code of Federal Regulations, 2010 CFR
2010-01-01
... each satisfactory test. A. Purity. B. Safety. C. Potency. D. Other tests. VI. Post preparatory steps. A... test. A. Purity. B. Safety. C. Potency. D. Moisture, if desiccated. E. Any other tests. VI. Post.... Potency. D. Any other tests. E. Include any additional pertinent information. IV. Post preparatory steps...
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9 CFR 114.9 - Outline of Production guidelines.
Code of Federal Regulations, 2012 CFR
2012-01-01
... each satisfactory test. A. Purity. B. Safety. C. Potency. D. Other tests. VI. Post preparatory steps. A... test. A. Purity. B. Safety. C. Potency. D. Moisture, if desiccated. E. Any other tests. VI. Post.... Potency. D. Any other tests. E. Include any additional pertinent information. IV. Post preparatory steps...
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9 CFR 114.9 - Outline of Production guidelines.
Code of Federal Regulations, 2013 CFR
2013-01-01
... each satisfactory test. A. Purity. B. Safety. C. Potency. D. Other tests. VI. Post preparatory steps. A... test. A. Purity. B. Safety. C. Potency. D. Moisture, if desiccated. E. Any other tests. VI. Post.... Potency. D. Any other tests. E. Include any additional pertinent information. IV. Post preparatory steps...
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9 CFR 114.9 - Outline of Production guidelines.
Code of Federal Regulations, 2011 CFR
2011-01-01
... each satisfactory test. A. Purity. B. Safety. C. Potency. D. Other tests. VI. Post preparatory steps. A... test. A. Purity. B. Safety. C. Potency. D. Moisture, if desiccated. E. Any other tests. VI. Post.... Potency. D. Any other tests. E. Include any additional pertinent information. IV. Post preparatory steps...
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9 CFR 114.9 - Outline of Production guidelines.
Code of Federal Regulations, 2014 CFR
2014-01-01
... each satisfactory test. A. Purity. B. Safety. C. Potency. D. Other tests. VI. Post preparatory steps. A... test. A. Purity. B. Safety. C. Potency. D. Moisture, if desiccated. E. Any other tests. VI. Post.... Potency. D. Any other tests. E. Include any additional pertinent information. IV. Post preparatory steps...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-02-16
...] Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products; Availability AGENCY: Food and... the availability of a document entitled ``Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products'' dated January 2011. The guidance document provides manufacturers of cellular and gene...
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Potency determination is important to identify the most promising drug candidates as well as identification of and ranking of compound toxicity. In our laboratory, we have utilized MEA recording techniques to determine the relative potency of 11 insecticidal compounds and rank th...
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21 CFR 660.22 - Potency requirements with reference preparations.
Code of Federal Regulations, 2011 CFR
2011-04-01
... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Potency requirements with reference preparations. 660.22 Section 660.22 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN.... Products for which reference Blood Grouping Reagents are available shall have a potency titer value at...
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21 CFR 660.22 - Potency requirements with reference preparations.
Code of Federal Regulations, 2010 CFR
2010-04-01
... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Potency requirements with reference preparations. 660.22 Section 660.22 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN.... Products for which reference Blood Grouping Reagents are available shall have a potency titer value at...
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21 CFR 640.56 - Quality control test for potency.
Code of Federal Regulations, 2011 CFR
2011-04-01
..., Center for Biologics Evaluation and Research, Food and Drug Administration. Such testing shall not be... Evaluation and Research, Food and Drug Administration. (d) If the average potency level of antihemophilic... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Quality control test for potency. 640.56 Section...
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Hu, Jia; Liden, Robert C
2011-07-01
Integrating theories of self-regulation with team and leadership literatures, this study investigated goal and process clarity and servant leadership as 3 antecedents of team potency and subsequent team effectiveness, operationalized as team performance and organizational citizenship behavior. Our sample of 304 employees represented 71 teams in 5 banks. Results showed that team-level goal and process clarity as well as team servant leadership served as 3 antecedents of team potency and subsequent team performance and team organizational citizenship behavior. Furthermore, we found that servant leadership moderated the relationships between both goal and process clarity and team potency, such that the positive relationships between both goal and process clarity and team potency were stronger in the presence of servant leadership.
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Fukuda, Tadashi; Iwaki, Masaaki; Komiya, Takako; Shibayama, Keigo; Takahashi, Motohide; Nakashima, Hideki
2013-01-01
Haemophilus influenzae type b vaccine conjugated with tetanus toxoid (HibT) was licensed for use in childhood immunization in Japan in 2007. As adsorbed diphtheria-tetanus-acellular pertussis (DTaP) combined with HibT vaccine has not been introduced in Japan, DTaP and HibT vaccines are injected at separate sites with a similar immunization schedule. There are various interfering or stimulatory effects between components of combined vaccines contained in DTaP and HibT vaccines. In this study, we investigated the effect of HibT containing combination vaccines on anti-tetanus potencies by using animal models (mouse, guinea pig, and rat). HibT vaccine and HibT components of imported DTaP-HibT vaccine alone showed comparable or higher anti-tetanus potency than DTaP vaccine and DTaP-containing components of combination vaccines. Mixing these components before injection resulted in potencies greater than the sum of individual potencies. Injecting individual components at separate sites in animals resulted in potency roughly equivalent to the sum of the individual potencies. These results provide useful information regarding the use of HibT-containing multivalent vaccines in childhood immunization.
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Guirro, Rinaldo Roberto de Jesus; Weis, Luciana Cezimbra
2009-08-01
The main objectives of this study were to characterize low-level laser therapy (LLLT) and the physical therapy clinical procedures for its use. There are few scientific studies that characterize the calibration of LLLT equipment. Forty lasers at 36 physical therapy clinics were selected. The equipment was characterized through data collected from the owner manuals, direct consultation with the manufacturers, and a questionnaire answered by the users. A digital potency analyzer was used to calibrate released mean potency. Qualitative data were presented throughout the descriptive statistics and quantitative data were analyzed by the Wilcoxon/Kruskal-Wallis and Fisher tests (significance, p < 0.05). The laser equipment was either AsGa (70.5%) or HeNe (23.5%), and 60% was analog and acquired over 5 years ago. The majority of the equipment was used 10-15 times per week and the most frequent density level used was 2 to 4 J/cm(2). Protective goggles were available in only 19.4% of the clinics evaluated. The association between the analyzed categories demonstrated that a lower mean potency was correlated both with equipment acquired over 5 years ago and analog technology. The determined mean potency was lower than the one claimed by the manufacturer (p < 0.05). In 30 cases, the analyzed equipment presented a potency between 3 microW and 5.6 mW; in three cases, the potency was >25 mW; and in seven cases, potency was nonexistent. The analyzed equipment was out-dated and periodical maintenance was not conducted, which was reflected in the low irradiated potency.
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21 CFR 640.56 - Quality control test for potency.
Code of Federal Regulations, 2010 CFR
2010-04-01
... quality control test for potency may be performed by a clinical laboratory which meets the standards of... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Quality control test for potency. 640.56 Section...) BIOLOGICS ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS Cryoprecipitate § 640.56 Quality control...
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Code of Federal Regulations, 2013 CFR
2013-04-01
... 21 Food and Drugs 7 2013-04-01 2013-04-01 false Potency test. 660.4 Section 660.4 Food and Drugs... STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Antibody to Hepatitis B Surface Antigen § 660.4 Potency test. To be satisfactory for release, each filling of Antibody to Hepatitis B Surface Antigen...
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Code of Federal Regulations, 2013 CFR
2013-04-01
... 21 Food and Drugs 7 2013-04-01 2013-04-01 false Potency test. 660.43 Section 660.43 Food and Drugs... STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Hepatitis B Surface Antigen § 660.43 Potency test... antibody in the appropriate sera of the reference panel by all test methods recommended by the manufacturer...
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Fragrances Categorized According to Relative Human Skin Sensitization Potency
Api, Anne Marie; Parakhia, Rahul; O'Brien, Devin; Basketter, David A.
2017-01-01
Background The development of non-animal alternatives for skin sensitization potency prediction is dependent upon the availability of a sufficient dataset whose human potency is well characterized. Previously, establishment of basic categorization criteria for 6 defined potency categories, allowed 131 substances to be allocated into them entirely on the basis of human information. Objectives To supplement the original dataset with an extended range of fragrance substances. Methods A more fully described version of the original criteria was used to assess 89 fragrance chemicals, allowing their allocation into one of the 6 potency categories. Results None of the fragrance substances were assigned to the most potent group, category 1, whereas 11 were category 2, 22 were category 3, 37 were category 4, and 19 were category 5. Although none were identified as non-sensitizing, note that substances in category 5 also do not pass the threshold for regulatory classification. Conclusions The combined datasets of >200 substances placed into potency categories solely on the basis of human data provides an essential resource for the elaboration and evaluation of predictive non-animal methods. PMID:28691948
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Blackwell, Brett R.; Ankley, Gerald T.; Corsi, Steven; DeCicco, Laura; Houck, Kieth A.; Judson, Richard S.; Li, Shibin; Martin, Matthew T.; Murphy, Elizabeth; Schroeder, Anthony L.; Smith, Edwin R.; Swintek, Joe; Villeneuve, Daniel L.
2017-01-01
Current environmental monitoring approaches focus primarily on chemical occurrence. However, based on concentration alone, it can be difficult to identify which compounds may be of toxicological concern and should be prioritized for further monitoring, in-depth testing, or management. This can be problematic because toxicological characterization is lacking for many emerging contaminants. New sources of high-throughput screening (HTS) data, such as the ToxCast database, which contains information for over 9000 compounds screened through up to 1100 bioassays, are now available. Integrated analysis of chemical occurrence data with HTS data offers new opportunities to prioritize chemicals, sites, or biological effects for further investigation based on concentrations detected in the environment linked to relative potencies in pathway-based bioassays. As a case study, chemical occurrence data from a 2012 study in the Great Lakes Basin along with the ToxCast effects database were used to calculate exposure–activity ratios (EARs) as a prioritization tool. Technical considerations of data processing and use of the ToxCast database are presented and discussed. EAR prioritization identified multiple sites, biological pathways, and chemicals that warrant further investigation. Prioritized bioactivities from the EAR analysis were linked to discrete adverse outcome pathways to identify potential adverse outcomes and biomarkers for use in subsequent monitoring efforts.
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Solid State Stability of Extemporaneously Prepared Levothyroxine Aliquots and Capsules.
Fortner, Jeff; Salton, Jason; Carlson, Christie; Wheeler, Rich; Cote, Brianna; Rao, Deepa
2015-01-01
The purpose of this research was to collect, analyze, and compare stability data for levothyroxine (T4) powder in the anhydrous and pentahydrate form when prepared as an aliquot and in capsules. Two different compounding pharmacies, Central Iowa Compounding and Gateway Medical Pharmacy, used different forms of T4 and aliquot formulations, which were studied to determine the beyond-use date at ±5% or ±10% of labeled strength. T4 was extracted from aliquot and capsule formulations and assessed using reverse-phase high- performance liquid chromatography validated to differentiate between the degraded and original forms of T4. The results indicate that T4 1:100 aliquot formulation prepared with silica gel or Avicel as filler are stable for 120 days at ±10% labeled potency, but at ±5% labeled potency, the silica gel and Avicel aliquot formulations are stable for 45 and 30 days, respectively. The silica gel capsules prepared from fresh aliquot were stable for 120 days at ±10% labeled potency and 90 days at ±5% labeled potency, while the Avicel capsules prepared from fresh aliquot were stable for 180 days at both ±10% and ±5% labeled potency. Avicel capsules prepared from old aliquot (120 days) and fresh aliquot (1 day) were also compared for stability. The old aliquot Avicel capsules were stable for 14 days at ±5% labeled potency and 150 days at ±10% labeled potency, while new aliquot Avicel capsules were stable for 180 days at both ±10% and ±5% labeled potency. Based on our data, there can be significant variation in the beyond-use dates assigned to T4 capsules based on the diluents used for aliquots, the final capsule formulations, and the potency standards applied. These results also indicate that pharmacists must exercise caution when using older aliquots and may have to assign shorter beyond-use dates.
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Assessment of the skin sensitising potency of the lower alkyl methacrylate esters.
Kimber, Ian; Pemberton, Mark A
2014-10-01
There is continued interest in, and imperatives for, the classification of contact allergens according to their relative skin sensitising potency. However, achieving that end can prove problematic, not least when there is an apparent lack of concordance between experimental assessments of potency and the prevalence allergic contact dermatitis as judged by clinical experience. For the purpose of exploring this issue, and illustrating the important considerations that are required to reach sound judgements about potency categorisation, the lower alkyl methacrylate esters (LAM) have been employed here as a case study. Although the sensitising potential of methyl methacrylate (MMA) has been reviewed previously, there is available new information that is relevant for assessment of skin sensitising potency. Moreover, for the purposes of this article, analyses have been extended to include also other LAM for which relevant data are available: ethyl methacrylate (EMA), n-butyl methacrylate (nBMA), isobutyl methacrylate (iBMA), and 2-ethylhexyl methacrylate (EHMA). In addressing the skin sensitising activity of these chemicals and in drawing conclusions regarding relative potency, a number of sources of information has been considered, including estimates of potency derived from local lymph node assay (LLNA) data, the results of guinea pig assays, and data derived from in silico methods and from recently developed in vitro approaches. Moreover, clinical experience of skin sensitisation of humans by LAM has also been evaluated. The conclusion drawn is that MMA and other LAM are contact allergens, but that none of these chemicals has any more than weak skin sensitising potency. We have also explored here the possible bases for this modest sensitising activity. Finally, the nature of exposure to LAM has been reviewed briefly and on the basis of that information, together with an understanding of skin sensitising potency, a risk assessment has been prepared. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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Gross, S; Janssen, S W J; de Vries, B; Terao, E; Daas, A; Buchheit, K-H
2009-10-01
The European Pharmacopoeia (Ph. Eur.) monograph Human tetanus immunoglobulin (0398) gives a clear outline of the in vivo assay to be performed to determine the potency of human tetanus immunoglobulins during their development. Furthermore, it states that an in vitro method shall be validated for the batch potency estimation. Since no further guidance is given on the in vitro assay, every control laboratory concerned is free to design and validate an in-house method. At the moment there is no agreed in vitro method available. The aim of this study was to validate and compare 2 alternative in vitro assays, i.e. an enzyme-linked immunoassay (EIA) and a toxoid inhibition assay (TIA), through an international collaborative study, in view of their eventual inclusion into the Ph. Eur.. The study was run in the framework of the Biological Standardisation Programme (BSP), under the aegis of the European Commission and the Council of Europe. The collaborative study reported here involved 21 laboratories (public and industry) from 15 countries. Initially, 3 samples with low, medium and high potencies were tested by EIA and TIA. Results showed good reproducibility and repeatability of the 2 in vitro methods. The correlation of the data with the in vivo potency assigned by the manufacturers however appeared initially poor for high potency samples. Thorough re-examination of the data showed that the in vivo potencies assigned by the manufacturers had to be corrected: one for potency loss at the time of in vitro testing and one because of a reporting error. After these corrections the values obtained by in vivo and in vitro methods were in close agreement. A supplementary collaborative work was carried out to validate the 2 methods for immunoglobulin products with high potencies. Eight laboratories (public and industry) took part in this additional study to test 3 samples with medium and high potencies by EIA and TIA. Results confirmed that the 2 alternative methods are comparable in terms of assay repeatability, precision and reproducibility. In all laboratories, both methods discriminated between the low, medium and high potency samples. Analysis of the data collected in this study showed a good correlation between EIA and TIA potency estimates as well as a close agreement between values obtained by in vitro and in vivo methods. The study demonstrated that EIA and TIA are suitable quality control methods for polyclonal human tetanus immunoglobulin, which can be standardised in a quality control laboratory using a quality assurance system. Consequently, the Ph. Eur. Group of Experts 6B on Human Blood and Blood products decided in April 2009 to include both methods as examples in the Ph. Eur. monograph 0398 on Human Tetanus immunoglobulin.
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Non-animal methods to predict skin sensitization (I): the Cosmetics Europe database.
Hoffmann, Sebastian; Kleinstreuer, Nicole; Alépée, Nathalie; Allen, David; Api, Anne Marie; Ashikaga, Takao; Clouet, Elodie; Cluzel, Magalie; Desprez, Bertrand; Gellatly, Nichola; Goebel, Carsten; Kern, Petra S; Klaric, Martina; Kühnl, Jochen; Lalko, Jon F; Martinozzi-Teissier, Silvia; Mewes, Karsten; Miyazawa, Masaaki; Parakhia, Rahul; van Vliet, Erwin; Zang, Qingda; Petersohn, Dirk
2018-05-01
Cosmetics Europe, the European Trade Association for the cosmetics and personal care industry, is conducting a multi-phase program to develop regulatory accepted, animal-free testing strategies enabling the cosmetics industry to conduct safety assessments. Based on a systematic evaluation of test methods for skin sensitization, five non-animal test methods (DPRA (Direct Peptide Reactivity Assay), KeratinoSens TM , h-CLAT (human cell line activation test), U-SENS TM , SENS-IS) were selected for inclusion in a comprehensive database of 128 substances. Existing data were compiled and completed with newly generated data, the latter amounting to one-third of all data. The database was complemented with human and local lymph node assay (LLNA) reference data, physicochemical properties and use categories, and thoroughly curated. Focused on the availability of human data, the substance selection resulted nevertheless resulted in a high diversity of chemistries in terms of physico-chemical property ranges and use categories. Predictivities of skin sensitization potential and potency, where applicable, were calculated for the LLNA as compared to human data and for the individual test methods compared to both human and LLNA reference data. In addition, various aspects of applicability of the test methods were analyzed. Due to its high level of curation, comprehensiveness, and completeness, we propose our database as a point of reference for the evaluation and development of testing strategies, as done for example in the associated work of Kleinstreuer et al. We encourage the community to use it to meet the challenge of conducting skin sensitization safety assessment without generating new animal data.
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Zaghi, Danny; Maibach, Howard I
2009-01-01
The human maximization test (HMT) is a method to evaluate potency in humans, while the local lymph node assay (LLNA) is a test method that allows for the measuring of the allergic potency of a substance in a rodent. It has been proposed that an EC3 value (the value obtained by the LLNA test, ie, the concentration of an allergen leading to a 3-fold increase of baseline proliferation rate) would be a reliable indicator for a compound's allergic potency in humans. This paper compares the correlation between the EC3 value of a compound and its allergic occurrence in the general population with the correlation between the HMT of the compound and its allergic occurrence in the general population, to determine the relationship to potency. The correlation values when outliers were removed from the sample were -0.56 and -0.71 for LLNA and HMT, respectively, suggesting that there is a possible 20% error margin in LLNA's ability to predict potency. The data also suggest that other factors (such as exposure) could play up to a 30% role in the determination of allergic occurrence in the general population. The potency assays might be made more clinically relevant for predicting allergic frequencies by including a frequency factor and other factors in its dermatotoxicological interpretation.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Bates, John T.; Keefer, Christopher J.; Slaughter, James C.
2014-04-15
The role of binding kinetics in determining neutralizing potency for antiviral antibodies is poorly understood. While it is believed that increased steady-state affinity correlates positively with increased virus-neutralizing activity, the relationship between association or dissociation rate and neutralization potency is unclear. We investigated the effect of naturally-occurring antibody resistance mutations in the RSV F protein on the kinetics of binding to palivizumab. Escape from palivizumab-mediated neutralization of RSV occurred with reduced association rate (K{sub on}) for binding to RSV F protein, while alteration of dissociation rate (K{sub off}) did not significantly affect neutralizing activity. Interestingly, linkage of reduced K{sub on}more » with reduced potency mirrored the effect of increased K{sub on} found in a high-affinity enhanced potency palivizumab variant (motavizumab). These data suggest that association rate is the dominant factor driving neutralization potency for antibodies to RSV F protein antigenic site A and determines the potency of antibody somatic variants or efficiency of escape of viral glycoprotein variants. - Highlights: • The relationship of affinity to neutralization for virus antibodies is uncertain. • Palivizumab binds to RSV escape mutant fusion proteins, but with reduced affinity. • Association rate (K{sub on}) correlated well with the potency of neutralization.« less
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A comparative potency method for cancer risk assessment has been developed based upon a constant relative potency hypothesis. This method was developed and tested using data from a battery of short-term mutagenesis bioassays, animal tumorigenicity data and human lung cancer risk ...
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Sonnenburg, Anna; Schreiner, Maximilian; Stahlmann, Ralf
2015-12-01
Parabens, methylisothiazolinone (MI) and its derivative methylchloroisothiazolinone (MCI), are commonly used as preservatives in personal care products. They can cause hypersensitivity reactions of the human skin. We have tested a set of nine parabens, MI alone and in combination with MCI in the loose-fit coculture-based sensitization assay (LCSA). The coculture of primary human keratinocytes and allogenic dendritic cell-related cells (DC-rc) in this assay emulates the in vivo situation of the human skin. Sensitization potency of the test substances was assessed by flow cytometric analysis of the DC-rc maturation marker CD86. Determination of the concentration required to cause a half-maximal increase in CD86-expression (EC50sens) allowed a quantitative evaluation. The cytotoxicity of test substances as indicator for irritative potency was measured by 7-AAD (7-amino-actinomycin D) staining. Parabens exhibited weak (methyl-, ethyl-, propyl- and isopropylparaben) or strong (butyl-, isobutyl-, pentyl- and benzylparaben) effects, whereas phenylparaben was found to be a moderate sensitizer. Sensitization potencies of parabens correlated with side chain length. Due to a pronounced cytotoxicity, we could not estimate an EC50sens value for MI, whereas MI/MCI was classified as sensitizer and also showed cytotoxic effects. Parabens showed no (methyl- and ethylparaben) or weak irritative potencies (propyl-, isopropyl-, butyl-, isobutyl-, phenyl- and benzylparaben), only pentylparaben was rated to be irritative. Overall, we were able to demonstrate and compare the sensitizing potencies of parabens in this in vitro test. Furthermore, we showed an irritative potency for most of the preservatives. The data further support the usefulness of the LCSA for comparison of the sensitizing potencies of xenobiotics.
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Biological and chemical analysis of the toxic potency of pesticides in rainwater.
Hamers, T; Smit, M G; Murk, A J; Koeman, J H
2001-11-01
A newly developed method for measuring the integrated esterase inhibiting potency of rainwater samples was applied in practice, and the results are compared to the toxic potency calculated from concentrations of 31 organophosphate (OP) and carbamate pesticides, out of a total of 66 chemically analyzed pesticides. In addition, the general toxic potency of the rainwater samples was evaluated in a microtiter luminescence assay with Vibrio fischeri bacteria. Rainwater samples were collected over four consecutive 14-day periods in both open and wet-only samplers. The esterase inhibiting potency of the open rainwater samples (expressed as ng dichlorvos-equivalents/l) corresponded well with the chemical analyses of the rainwater samples collected by both types of samplers (r = 0.83-0.86). By far, the highest esterase inhibiting potency was found in a sample collected in an area with intense horticultural activities in June, and was attributed to high concentrations of dichlorvos, mevinphos, pirimiphos-methyl and methiocarb. The esterase inhibiting potency of this sample was equivalent to a dichlorvos concentration of 1380 ng/l in the rainwater, which is almost 2000 times higher than the maximum permissible concentration (MPC) of dichlorvos set for surface water in Netherlands. Maximum individual concentrations of dichlorvos and pirimiphos-methyl even exceeded the EC50 for Daphnia, suggesting that pesticides in rainwater pose a risk for aquatic organisms. Not all responses of the luminescence-assay for general toxicity could be explained by the analyzed pesticide concentrations. The bio-assays enable a direct assessment the toxic potency of all individual compounds present in the complex mixture of rainwater pollutants, even if they are unknown or present at concentrations below the detection limit. Therefore, they are valuable tools for prescreening and hazard characterization purposes.
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In vitro and in vivo potency of insulin analogues designed for clinical use.
Vølund, A; Brange, J; Drejer, K; Jensen, I; Markussen, J; Ribel, U; Sørensen, A R; Schlichtkrull, J
1991-11-01
Analogues of human insulin designed to have improved absorption properties after subcutaneous injection have been prepared by recombinant DNA technology. Five rapidly absorbed analogues, being predominantly in mono- or di-meric states in the pharmaceutical preparation, and a hexameric analogue with very low solubility at neutral pH and slow absorption, were studied. Receptor binding assays with HEP-G2 cells showed overall agreement with mouse free adipocyte assays. Two analogues, B28Asp and A21Gly + B27Arg + B30Thr-NH2, had nearly the same molar in vitro potency as human insulin. Another two showed increased adipocyte potency and receptor binding, B10Asp 194% and 333% and A8His + B4His + B10Glu + B27His 575% and 511%, while B9Asp + B27Glu showed 29% and 18% and the B25Asp analogue only 0.12% and 0.05% potency. Bioassays in mice or rabbits of the analogues except B25Asp showed that they had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation in in vivo potency reflects the differences in receptor binding affinity. Relative to human insulin a low concentration is sufficient for a high affinity analogue to produce a given receptor complex formation and metabolic response. In conclusion, human insulin and analogues with markedly different in vitro potencies were equipotent in terms of hypoglycaemic effect. This is in agreement with the concept that elimination of insulin from blood and its subsequent degradation is mediated by insulin receptors.
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Das, Pronay; Babbar, Palak; Malhotra, Nipun; Sharma, Manmohan; Jachak, Gorakhnath R; Gonnade, Rajesh G; Shanmugam, Dhanasekaran; Harlos, Karl; Yogavel, Manickam; Sharma, Amit; Reddy, D Srinivasa
2018-05-21
The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332. Given that scores of anti-malarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of anti-microbial drug development.
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Zscan4 restores the developmental potency of embryonic stem cells
Amano, Tomokazu; Hirata, Tetsuya; Falco, Geppino; Monti, Manuela; Sharova, Lioudmila V.; Amano, Misa; Sheer, Sarah; Hoang, Hien G.; Piao, Yulan; Stagg, Carole A.; Yamamizu, Kohei; Akiyama, Tomohiko; Ko, Minoru S.H.
2013-01-01
The developmental potency of mouse embryonic stem (ES) cells, which is the ability to contribute to a whole embryo is known to deteriorate during long-term cell culture. Previously we have shown that ES cells oscillate between Zscan4- and Zscan4+ states, and the transient activation of Zscan4 is required for the maintenance of telomeres and genome stability of ES cells. Here we show that increasing the frequency of Zscan4 activation in mouse ES cells restores and maintains their developmental potency in long-term cell culture. Injection of a single ES cell with such increased potency into a tetraploid blastocyst gives rise to an entire embryo with a higher success rate. These results not only provide a means to rejuvenate ES cells by manipulating Zscan4 expression, but also indicate the active roles of Zscan4 in the long-term maintenance of ES cell potency. PMID:23739662
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Is it useful to add acetaminophen to high-potency opioids in cancer-related pain?
Corsi, Oscar; Pérez-Cruz, Pedro E
2017-05-04
Pain is one of the most frequent and relevant symptoms in cancer patients. The World Health Organization's analgesic ladder proposes the use of strong opioids associated with adjuvants such as acetaminophen or nonsteroidal anti-inflammatory drugs in step III. However, it is unclear whether adding acetaminophen to an analgesic regimen based on strong opioids has any benefit in cancer patients with moderate to severe pain. To answer this question we searched in Epistemonikos database, which is maintained by screening multiple information sources. We identified two systematic reviews including five randomized trials overall. We extracted data and generated a summary of findings table using the GRADE approach. We concluded that adding acetaminophen to strong opioids might make little or no difference in improving pain management in cancer patients.
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Tautomerism, Hammett σ, and QSAR
NASA Astrophysics Data System (ADS)
Martin, Yvonne Connolly
2010-06-01
A consideration of equilibrium model-based equations suggests that tautomeric equilibria do not markedly affect observed potency if the tautomer bound represents at least 50% of the compound in solution. Tautomeric equilibria can enhance or attenuate the correlation of potency with Hammett σ. Additionally, tautomeric equilibria can lead to a correlation of potency with σ even in the absence of a correlation of binding with σ.
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Quality of original and biosimilar epoetin products.
Brinks, Vera; Hawe, Andrea; Basmeleh, Abdul H H; Joachin-Rodriguez, Liliana; Haselberg, Rob; Somsen, Govert W; Jiskoot, Wim; Schellekens, Huub
2011-02-01
To compare the quality of therapeutic erythropoietin (EPO) products, including two biosimilars, with respect to content, aggregation, isoform profile and potency. Two original products, Eprex (epoetin alpha) and Dynepo (epoetin delta), and two biosimilar products, Binocrit (epoetin alpha) and Retacrit (epoetin zeta), were compared using (1) high performance size exclusion chromatography, (2) ELISA, (3) SDS-PAGE, (4) capillary zone electrophoresis and (5) in-vivo potency. Tested EPO products differed in content, isoform composition, and potency. Of the tested products, the biosimilars have the same or even better quality as the originals. Especially, the potency of originals may significantly differ from the value on the label.
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Ghaznavi, Amir M; Nakamura, Mio; Tepper, Donna
2015-01-01
Sclerotherapy is the treatment of reticular veins and telangiectasias of the lower extremities. Sclerosants destroy endothelial tissue and expose subendothelial collagen fibers, which lead to subsequent fibrosis of vessels, thus preventing recanalization. There are several available sclerosants including sodium tetradecyl sulfate (STS), polidocanol (POL), and chromated glycerin (CG) with varying efficacy, potency, side effect profile, and cost. To identify the possible bacterial contamination and potency of CG beyond the current recommended shelf life of 3 months and to prove if CG is as cost effective as other available sclerosants. Samples of 72% CG underwent bacterial endotoxin, sterility, and potency analysis at Days 0, 24, and 183. In addition, cost comparison was performed with other commercially available sclerosants including STS and POL. No samples of CG showed any bacterial contamination. All aliquots of glycerin remained sterile at Day 14. Potency at Day 24 was 99.2%, which was the same at Day 183. Cost comparison with other sclerosants revealed that CG is lower cost per milliliter than STS and POL. Seventy-two percent CG has no contamination and maintains its reported potency up to 6 months while comparable with the cost of other commercially available sclerosants.
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Sawada, T; Karaki, K; Hayashi, T; Yoneyama, S; Mizushima, Y; Moriyama, T; Nishimura, K; Kimura, Y; Nakano, M; Kato, I
2001-05-01
To evaluate the repeated oral dose toxicity of Cefmatilen hydrochloride hydrate (S-1090) in juvenile dogs, S-1090 was administered to juvenile beagle dogs at dose levels of 50, 100, 200 and 400 mg potency/kg/day for 3 months. No deaths occurred. Urinalysis in the 400 mg potency/kg group revealed positive reactions of occult blood and protein, and erythrocytes in sediments. Cystitis was observed in the 200 and 400 mg potency/kg groups. In the thyroids, an increased weight in some animals in the groups dosed at 100 mg potency/kg or more and an increased follicular colloid in the 400 mg potency/kg group were observed. However, no related changes were noted in other examination items. Red to dark-red feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet) were observed in all treated groups. Plasma S-1090 concentrations increased in a manner less than dose-proportional. The lesions of urinary bladder were judged as S-1090-induced toxic changes and the NOAEL of S-1090 in this study was assessed to be 100 mg potency/kg/day.
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Francisco, Fabiane Lacerda; Saviano, Alessandro Morais; Almeida, Túlia de Souza Botelho; Lourenço, Felipe Rebello
2016-05-01
Microbiological assays are widely used to estimate the relative potencies of antibiotics in order to guarantee the efficacy, safety, and quality of drug products. Despite of the advantages of turbidimetric bioassays when compared to other methods, it has limitations concerning the linearity and range of the dose-response curve determination. Here, we proposed to use partial least squares (PLS) regression to solve these limitations and to improve the prediction of relative potencies of antibiotics. Kinetic-reading microplate turbidimetric bioassays for apramacyin and vancomycin were performed using Escherichia coli (ATCC 8739) and Bacillus subtilis (ATCC 6633), respectively. Microbial growths were measured as absorbance up to 180 and 300min for apramycin and vancomycin turbidimetric bioassays, respectively. Conventional dose-response curves (absorbances or area under the microbial growth curve vs. log of antibiotic concentration) showed significant regression, however there were significant deviation of linearity. Thus, they could not be used for relative potency estimations. PLS regression allowed us to construct a predictive model for estimating the relative potencies of apramycin and vancomycin without over-fitting and it improved the linear range of turbidimetric bioassay. In addition, PLS regression provided predictions of relative potencies equivalent to those obtained from agar diffusion official methods. Therefore, we conclude that PLS regression may be used to estimate the relative potencies of antibiotics with significant advantages when compared to conventional dose-response curve determination. Copyright © 2016 Elsevier B.V. All rights reserved.
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Hoffmann, Sebastian
2015-01-01
The development of non-animal skin sensitization test methods and strategies is quickly progressing. Either individually or in combination, the predictive capacity is usually described in comparison to local lymph node assay (LLNA) results. In this process the important lesson from other endpoints, such as skin or eye irritation, to account for variability reference test results - here the LLNA - has not yet been fully acknowledged. In order to provide assessors as well as method and strategy developers with appropriate estimates, we investigated the variability of EC3 values from repeated substance testing using the publicly available NICEATM (NTP Interagency Center for the Evaluation of Alternative Toxicological Methods) LLNA database. Repeat experiments for more than 60 substances were analyzed - once taking the vehicle into account and once combining data over all vehicles. In general, variability was higher when different vehicles were used. In terms of skin sensitization potential, i.e., discriminating sensitizer from non-sensitizers, the false positive rate ranged from 14-20%, while the false negative rate was 4-5%. In terms of skin sensitization potency, the rate to assign a substance to the next higher or next lower potency class was approx.10-15%. In addition, general estimates for EC3 variability are provided that can be used for modelling purposes. With our analysis we stress the importance of considering the LLNA variability in the assessment of skin sensitization test methods and strategies and provide estimates thereof.
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NASA Astrophysics Data System (ADS)
De, Biplab; Adhikari, Indrani; Nandy, Ashis; Saha, Achintya; Goswami, Binoy Behari
2017-06-01
Design and development of antioxidant supplements constitute an essential aspect of research in order to derive molecules that would help to combat the free radical invasion to the human body and curb oxidative stress related diseases. The present work deals with the development of in silico models for a series of thiazolidine derivatives having antioxidant potential. The objective of the work is to obtain models that would help to design new thazolidine derivatives based on substituent modification and thereby predict their activity profile. The QSAR model thus developed helps in quantification of the extent of contribution of the various molecular fragments towards the activity of the molecules, while the 3D pharmacophore model provides a brief idea of the essential molecular features that help the molecules to interact with the neighbouring free radicals. Both the models have been extensively validated which ensures their predictive ability as well the potential to search molecular databases for selection of thiazolidine derivatives with potent antioxidant activity. The models can thus be utilised effectively for database searching with the aim to isolate active antioxidants belonging to the thiazolidine group.
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Single-cell entropy for accurate estimation of differentiation potency from a cell's transcriptome
NASA Astrophysics Data System (ADS)
Teschendorff, Andrew E.; Enver, Tariq
2017-06-01
The ability to quantify differentiation potential of single cells is a task of critical importance. Here we demonstrate, using over 7,000 single-cell RNA-Seq profiles, that differentiation potency of a single cell can be approximated by computing the signalling promiscuity, or entropy, of a cell's transcriptome in the context of an interaction network, without the need for feature selection. We show that signalling entropy provides a more accurate and robust potency estimate than other entropy-based measures, driven in part by a subtle positive correlation between the transcriptome and connectome. Signalling entropy identifies known cell subpopulations of varying potency and drug resistant cancer stem-cell phenotypes, including those derived from circulating tumour cells. It further reveals that expression heterogeneity within single-cell populations is regulated. In summary, signalling entropy allows in silico estimation of the differentiation potency and plasticity of single cells and bulk samples, providing a means to identify normal and cancer stem-cell phenotypes.
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Singhatanadgit, Weerachai; Varodomrujiranon, Manatsanan
2013-12-01
The present study aimed to investigate the osteogenic potency of scaffold-free 3-dimensional (3D) spheres of periodontal ligament stem cells (PDLSCs). The osteogenic potency of PDLSC spheres was determined by the ability to form mineralization and to express key osteogenesis-associated genes. The alkaline phosphatase (ALP) activity and the protein content of PDLSC spheres were also measured. The 3D sphere developed its osteogenic potency in a time-dependent manner, containing approximately 10-fold higher mineralization, 5-fold higher protein content, and 4-fold greater ALP activity than those in the controls. The expression of key osteogenic genes was also upregulated in the 3D PDLSC spheres. Cellular outgrowth was observed when reintroduced into 2D culture. PDLSCs were able to undergo osteogenic differentiation in a scaffold-free 3D culture, producing bonelike mineralization in vitro. This suggests, at least in vitro, the osteogenic potency of the 3D PDLSC spheres. Copyright © 2013 Elsevier Inc. All rights reserved.
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NASA Astrophysics Data System (ADS)
Reid, Andrew C. E.; Olson, Gregory B.
2000-03-01
Heterogeneous nucleation of martensite is modeled by examining the strain field of a dislocation array in a nonlinear, nonlocal continuum elastic matrix. The dislocations are modeled by including effects from atomic length scales, which control the dislocation Burger's vector, into a mesoscopic continuum model. The dislocation array models the heterogeneous nucleation source of the Olson/Cohen defect dissociation model, and depending on the potency can give rise to embryos of different character. High potency dislocations give rise to fully developed, classical pre-existing embryos, whereas low-potency dislocations result in the formation of highly nonclassical strain embryos. Heterogeneous nucleation theory is related to nucleation kinetics through the critical driving force for nucleation at a defect of a given potency. Recent stereological and calorimetric kinetic studies in thermoelastic TiNi alloys confirm that these materials exhibit the same form of defect potency distribution and resulting sample-size dependent Martensite start temperature, M_s, as nonthermoelastic FeNi systems. These results together point towards a broad theory of heterogeneous nucleation for both thermoelastic and nonthermoelastic martensites.
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Single-cell entropy for accurate estimation of differentiation potency from a cell's transcriptome
Teschendorff, Andrew E.; Enver, Tariq
2017-01-01
The ability to quantify differentiation potential of single cells is a task of critical importance. Here we demonstrate, using over 7,000 single-cell RNA-Seq profiles, that differentiation potency of a single cell can be approximated by computing the signalling promiscuity, or entropy, of a cell's transcriptome in the context of an interaction network, without the need for feature selection. We show that signalling entropy provides a more accurate and robust potency estimate than other entropy-based measures, driven in part by a subtle positive correlation between the transcriptome and connectome. Signalling entropy identifies known cell subpopulations of varying potency and drug resistant cancer stem-cell phenotypes, including those derived from circulating tumour cells. It further reveals that expression heterogeneity within single-cell populations is regulated. In summary, signalling entropy allows in silico estimation of the differentiation potency and plasticity of single cells and bulk samples, providing a means to identify normal and cancer stem-cell phenotypes. PMID:28569836
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The local lymph node assay and the assessment of relative potency: status of validation.
Basketter, David A; Gerberick, Frank; Kimber, Ian
2007-08-01
For the prediction of skin sensitization potential, the local lymph node assay (LLNA) is a fully validated alternative to guinea-pig tests. More recently, information from LLNA dose-response analyses has been used to assess the relative potency of skin sensitizing chemicals. These data are then deployed for risk assessment and risk management. In this commentary, the utility and validity of these relative potency measurements are reviewed. It is concluded that the LLNA does provide a valuable assessment of relative sensitizing potency in the form of the estimated concentration of a chemical required to produce a threefold stimulation of draining lymph node cell proliferation compared with concurrent controls (EC3 value) and that all reasonable validation requirements have been addressed successfully. EC3 measurements are reproducible in both intra- and interlaboratory evaluations and are stable over time. It has been shown also, by several independent groups, that EC3 values correlate closely with data on relative human skin sensitization potency. Consequently, the recommendation made here is that LLNA EC3 measurements should now be regarded as a validated method for the determination of the relative potency of skin sensitizing chemicals, a conclusion that has already been reached by a number of independent expert groups.
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Dodt, J; Hubbard, A R; Wicks, S J; Gray, E; Neugebauer, B; Charton, E; Silvester, G
2015-07-01
A workshop organized by the European Medicines Agency and the European Directorate for the Quality of Medicines and HealthCare was held in London, UK on November 28-29, 2013, to provide an overview of the current knowledge of the characterization of new factor VIII (FVIII) and factor IX (FIX) concentrates with respect to potency assays and testing of postinfusion material. The objective was to set the basis for regulatory authorities' discussion on the most appropriate potency assay for the individual products, and European Pharmacopoeia (Ph. Eur.) discussion on whether to propose revision of the Ph. Eur. monographs with respect to potency assays in the light of information on new FVIII and FIX concentrates. The workshop showed that for all products valid assays vs. the international concentrate standards were obtained and potency could be expressed in International Units. The Ph. Eur. chromogenic potency assay gave valid assay results which correlate with in vivo functionality of rFVIII products. For some modified rFVIII products and all modified rFIX products, one-stage clotting assay methods result in different potencies depending on the activated partial thromboplastin time reagent. As a consequence, monitoring of patients' postinfusion levels is challenging but it was pointed out that manufacturers are responsible for providing the users with appropriate information for use and laboratory testing of their product. Strategies to avoid misleading determination of patents' plasma levels, e.g. information on suitable assays, laboratory standards or correction factors were discussed. © 2015 John Wiley & Sons Ltd.
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Kato, I; Sato, K; Ueno, M; Inoue, S; Harihara, A; Moriyama, T; Nishimura, K; Yabuuchi, K; Hirata, M; Muraoka, Y; Kitamura, T; Furukawa, H
2001-05-01
One- or three-month repeated oral dose toxicity studies of Cefmatilen hydrochloride hydrate (S-1090) in rats were conducted. Doses were set at 80, 200, 500 and 1250 mg potency/kg/day in the one-month toxicity study, and 100, 300 and 1000 mg potency/kg/day in the three-month toxicity study. Body weights increased favorably and no deaths occurred in all treated groups of both studies. The changes observed in both studies were soft feces, abdominal distention, increased food and water consumption, decreases of urine volume and pH, and a decrease of blood neutrophils in almost all treated groups, reddish-brown feces (due to chelated products of S-1090 and its decomposition products with Fe3+ in the diet) in groups dosed at 300 mg potency/kg or more, and a lower mature granulocyte ratio in the bone marrow in groups dosed at 1000 mg potency/kg or more. In necropsy, cecal enlargement with a large amount of muddy content was observed in all treated groups of both studies. In the three-month toxicity study, elevated drug-metabolizing enzyme activities were noted in the liver of the males in the 1000 mg potency/kg group. These changes were slight except for the cecal enlargement and the rats recovered well with drug withdrawal. Since no toxicologically significant changes were noted in either study, the NOAEL of S-1090 was estimated to be 1250 mg potency/kg/day in the one-month toxicity study and 1000 mg potency/kg/day in the three-month toxicity study.
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Engineering high-potency R-spondin adult stem cell growth factors.
Warner, Margaret L; Bell, Tufica; Pioszak, Augen A
2015-01-01
Secreted R-spondin proteins (RSPOs1-4) function as adult stem cell growth factors by potentiating Wnt signaling. Simultaneous binding of distinct regions of the RSPO Fu1-Fu2 domain module to the extracellular domains (ECDs) of the LGR4 G protein-coupled receptor and the ZNRF3 transmembrane E3 ubiquitin ligase regulates Wnt receptor availability. Here, we examine the molecular basis for the differing signaling strengths of RSPOs1-4 using purified RSPO Fu1-Fu2, LGR4 ECD, and ZNRF3 ECD proteins in Wnt signaling and receptor binding assays, and we engineer novel high-potency RSPOs. RSPO2/3/4 had similar signaling potencies that were stronger than that of RSPO1, whereas RSPO1/2/3 had similar efficacies that were greater than that of RSPO4. The RSPOs bound LGR4 with affinity rank order RSPO4 > RSPO2/3 > RSPO1 and ZNRF3 with affinity rank order RSPO2/3 > > RSPO1 > RSPO4. An RSPO2-4 chimera combining RSPO2 ZNRF3 binding with RSPO4 LGR4 binding was a "Superspondin" that exhibited enhanced ternary complex formation and 10-fold stronger signaling potency than RSPO2 and efficacy equivalent to RSPO2. An RSPO4-1 chimera combining RSPO4 ZNRF3 binding with RSPO1 LGR4 binding was a "Poorspondin" that exhibited signaling potency similar to RSPO1 and efficacy equivalent to RSPO4. Conferring increased ZNRF3 binding upon RSPO4 with amino acid substitutions L56F, I58L, and I63M enhanced its signaling potency and efficacy. Our results reveal the molecular basis for RSPOs1-4 activity differences and suggest that signaling potency is determined by ternary complex formation ability, whereas efficacy depends on ZNRF3 recruitment. High-potency RSPOs may be of value for regenerative medicine and/or therapeutic applications. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
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Ogawa, Yasushi; Fawaz, Farah; Reyes, Candice; Lai, Julie; Pungor, Erno
2007-01-01
Parameter settings of a parallel line analysis procedure were defined by applying statistical analysis procedures to the absorbance data from a cell-based potency bioassay for a recombinant adenovirus, Adenovirus 5 Fibroblast Growth Factor-4 (Ad5FGF-4). The parallel line analysis was performed with a commercially available software, PLA 1.2. The software performs Dixon outlier test on replicates of the absorbance data, performs linear regression analysis to define linear region of the absorbance data, and tests parallelism between the linear regions of standard and sample. Width of Fiducial limit, expressed as a percent of the measured potency, was developed as a criterion for rejection of the assay data and to significantly improve the reliability of the assay results. With the linear range-finding criteria of the software set to a minimum of 5 consecutive dilutions and best statistical outcome, and in combination with the Fiducial limit width acceptance criterion of <135%, 13% of the assay results were rejected. With these criteria applied, the assay was found to be linear over the range of 0.25 to 4 relative potency units, defined as the potency of the sample normalized to the potency of Ad5FGF-4 standard containing 6 x 10(6) adenovirus particles/mL. The overall precision of the assay was estimated to be 52%. Without the application of Fiducial limit width criterion, the assay results were not linear over the range, and an overall precision of 76% was calculated from the data. An absolute unit of potency for the assay was defined by using the parallel line analysis procedure as the amount of Ad5FGF-4 that results in an absorbance value that is 121% of the average absorbance readings of the wells containing cells not infected with the adenovirus.
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Affinities and architecture of Devonian trunks of Prototaxites loganii.
Retallack, G J; Landing, Ed
2014-01-01
Devonian fossil logs of Prototaxites loganii have been considered kelp-like aquatic algae, rolled up carpets of liverworts, enormous saprophytic fungal fruiting bodies or giant lichens. Algae and rolled liverwort models cannot explain the proportions and branching described here of a complete fossil of Prototaxites loganii from the Middle Devonian (386 Ma) Bellvale Sandstone on Schunnemunk Mountain, eastern New York. The "Schunnemunk tree" was 8.83 m long and had six branches, each about 1 m long and 9 cm diam, on the upper 1.2 m of the main axis. The coalified outermost layer of the Schunnemunk trunk and branches have isotopic compositions (δ(13)CPDB) of -25.03 ± 0.13‰ and -26.17 ± 0.69‰, respectively. The outermost part of the trunk has poorly preserved invaginations above cortical nests of coccoid cells embraced by much-branched tubular cells. This histology is unlike algae, liverworts or vascular plants and most like lichen with coccoid chlorophyte phycobionts. Prototaxites has been placed within Basidiomycota but lacks clear dikaryan features. Prototaxites and its extinct order Nematophytales may belong within Mucoromycotina or Glomeromycota. © 2014 by The Mycological Society of America.
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Carbon and nitrogen isotopic compositions of alkyl porphyrins from the Triassic Serpiano oil shale
NASA Technical Reports Server (NTRS)
Chicarelli, M. I.; Hayes, J. M.; Popp, B. N.; Eckardt, C. B.; Maxwell, J. R.
1993-01-01
The carbon and nitrogen isotopic compositions of seven of the most abundant alkylporphyrins from the Serpiano oil shale (marine, Triassic) were determined. For the C31 and C32 butanoporphyrins, values of delta 13CPDB and delta 15NAIR averaged -24.0% and -3.1%. In contrast, the C31 and C32 methylpropanoporphyrins, DPEP, and a C30 13-nor etioporphyrin had delta 13C and delta 15N values averaging -27.5 and -3.3%, respectively. Carbon and nitrogen isotopic values for kerogen averaged -30.8 and -0.9, whereas those for total extract averaged -31.6, and -4.0%. The butanoporphyrins apparently derive from a biological source different from that giving rise to the other porphyrins, their 13C enrichment not being related to carbon isotopic fractionation accompanying diagenetic reactions. The delta 15N values for all the porphyrins indicate that the depletion of 15N observed in the kerogen is of primary origin. Consistent with the very high abundance of hopanoids and methyl hopanoids in the aliphatic hydrocarbon fraction, it is suggested that cyanobacterial fixation of N2 may have been the main cause of 15N depletion.
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Diploptene: an indicator of terrigenous organic carbon in Washington coastal sediments
NASA Technical Reports Server (NTRS)
Prahl, F. G.; Hayes, J. M.
1992-01-01
The pentacyclic triterpene 17 beta(H),21 beta(H)-hop-22(29)-ene (diploptene) occurs in sediments throughout the Columbia River drainage basin and off the southern coast of Washington state in concentrations comparable to long-chain plantwax n-alkanes. The same relationship is evident for diploptene and long-chain n-alkanes in soils from the Willamette Valley. Microorganisms indigenous to soils and soil erosion are indicated as the biological source and physical process, respectively, for diploptene in coastal sediments. Similarity between the stable carbon isotopic composition (delta 13CPDB) of diploptene isolated from soil in the Willamette Valley (-31.2 +/- 0.3%) and from sediments deposited throughout the Washington coastal environment (-31.2 +/- 0.5%) supports this argument. Values of delta for diploptene in river sediments are variable and 8-17% lighter, indicating that an additional biological source such as methane-oxidizing bacteria makes a significant contribution to the diploptene record in river sediments. Selective biodegradation resulting from a difference in the physicochemical association within eroded particles can explain the absence of the more-13C-depleted form of diploptene in Washington coastal sediments, but this mechanism remains unproven.
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Structure-Based Predictions of Activity Cliffs
Husby, Jarmila; Bottegoni, Giovanni; Kufareva, Irina; Abagyan, Ruben; Cavalli, Andrea
2015-01-01
In drug discovery, it is generally accepted that neighboring molecules in a given descriptors' space display similar activities. However, even in regions that provide strong predictability, structurally similar molecules can occasionally display large differences in potency. In QSAR jargon, these discontinuities in the activity landscape are known as ‘activity cliffs’. In this study, we assessed the reliability of ligand docking and virtual ligand screening schemes in predicting activity cliffs. We performed our calculations on a diverse, independently collected database of cliff-forming co-crystals. Starting from ideal situations, which allowed us to establish our baseline, we progressively moved toward simulating more realistic scenarios. Ensemble- and template-docking achieved a significant level of accuracy, suggesting that, despite the well-known limitations of empirical scoring schemes, activity cliffs can be accurately predicted by advanced structure-based methods. PMID:25918827
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Kutschenko, Anna; Reinert, Marie-Christine; Krez, Nadja; Liebetanz, David; Rummel, Andreas
2017-03-01
The highly potent Botulinum neurotoxins (BoNT) are successful drugs to treat neuromuscular disorders. Efforts are being made to further reduce the injected BoNT dose and to lengthen the interval between treatments. Detailed knowledge of the BoNT structure-activity relationship (SAR) allows combining the best features of the different BoNT serotypes. Of all seven BoNT serotypes A-G, BoNT/A displays the highest potency despite low neuronal binding affinity, while BoNT/B exhibits much higher affinity. Recently, a new BoNT/AB hybrid (AABB) was constructed comprising the catalytic and translocation domain of BoNT/A and the 50kDa cell binding domain of BoNT/B. Here, we compared BoNT/A wild-type (AAAA) and AABB with regard to ex vivo potency and in vivo potency, efficacy and duration of action using the mouse phrenic nerve hemidiaphragm assay and the murine running wheel assay, respectively. The ex vivo potency of AABB was found to be 8.4-fold higher than that of AAAA. For the latter, two and 5 pg each of AAAA and AABB, respectively, were bilaterally injected into the calf muscles and mouse running wheel performance was automatically monitored during the following weeks to determine potency, efficacy and duration. Mice displayed a dose-dependent impairment of running performance. AABB showed potency, efficacy and duration equal to AAAA demonstrating successful exchange of the cell binding domain. AABB might combine the higher potency and longer duration of BoNT/A with the target specificity for the autonomic nervous system of BoNT/B. AABB might therefore constitute an improved treatment option for acetylcholine-mediated autonomic disorders such as hypersalivation or hyperhidrosis. Copyright © 2016 Elsevier B.V. All rights reserved.
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Development and validation of a rapid, aldehyde dehydrogenase bright-based cord blood potency assay.
Shoulars, Kevin; Noldner, Pamela; Troy, Jesse D; Cheatham, Lynn; Parrish, Amanda; Page, Kristin; Gentry, Tracy; Balber, Andrew E; Kurtzberg, Joanne
2016-05-12
Banked, unrelated umbilical cord blood provides access to hematopoietic stem cell transplantation for patients lacking matched bone marrow donors, yet 10% to 15% of patients experience graft failure or delayed engraftment. This may be due, at least in part, to inadequate potency of the selected cord blood unit (CBU). CBU potency is typically assessed before cryopreservation, neglecting changes in potency occurring during freezing and thawing. Colony-forming units (CFUs) have been previously shown to predict CBU potency, defined as the ability to engraft in patients by day 42 posttransplant. However, the CFU assay is difficult to standardize and requires 2 weeks to perform. Consequently, we developed a rapid multiparameter flow cytometric CBU potency assay that enumerates cells expressing high levels of the enzyme aldehyde dehydrogenase (ALDH bright [ALDH(br)]), along with viable CD45(+) or CD34(+) cell content. These measurements are made on a segment that was attached to a cryopreserved CBU. We validated the assay with prespecified criteria testing accuracy, specificity, repeatability, intermediate precision, and linearity. We then prospectively examined the correlations among ALDH(br), CD34(+), and CFU content of 3908 segments over a 5-year period. ALDH(br) (r = 0.78; 95% confidence interval [CI], 0.76-0.79), but not CD34(+) (r = 0.25; 95% CI, 0.22-0.28), was strongly correlated with CFU content as well as ALDH(br) content of the CBU. These results suggest that the ALDH(br) segment assay (based on unit characteristics measured before release) is a reliable assessment of potency that allows rapid selection and release of CBUs from the cord blood bank to the transplant center for transplantation. © 2016 by The American Society of Hematology.
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Development and validation of a rapid, aldehyde dehydrogenase bright–based cord blood potency assay
Noldner, Pamela; Troy, Jesse D.; Cheatham, Lynn; Parrish, Amanda; Page, Kristin; Gentry, Tracy; Balber, Andrew E.; Kurtzberg, Joanne
2016-01-01
Banked, unrelated umbilical cord blood provides access to hematopoietic stem cell transplantation for patients lacking matched bone marrow donors, yet 10% to 15% of patients experience graft failure or delayed engraftment. This may be due, at least in part, to inadequate potency of the selected cord blood unit (CBU). CBU potency is typically assessed before cryopreservation, neglecting changes in potency occurring during freezing and thawing. Colony-forming units (CFUs) have been previously shown to predict CBU potency, defined as the ability to engraft in patients by day 42 posttransplant. However, the CFU assay is difficult to standardize and requires 2 weeks to perform. Consequently, we developed a rapid multiparameter flow cytometric CBU potency assay that enumerates cells expressing high levels of the enzyme aldehyde dehydrogenase (ALDH bright [ALDHbr]), along with viable CD45+ or CD34+ cell content. These measurements are made on a segment that was attached to a cryopreserved CBU. We validated the assay with prespecified criteria testing accuracy, specificity, repeatability, intermediate precision, and linearity. We then prospectively examined the correlations among ALDHbr, CD34+, and CFU content of 3908 segments over a 5-year period. ALDHbr (r = 0.78; 95% confidence interval [CI], 0.76-0.79), but not CD34+ (r = 0.25; 95% CI, 0.22-0.28), was strongly correlated with CFU content as well as ALDHbr content of the CBU. These results suggest that the ALDHbr segment assay (based on unit characteristics measured before release) is a reliable assessment of potency that allows rapid selection and release of CBUs from the cord blood bank to the transplant center for transplantation. PMID:26968535
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Rivera-Mariani, Félix E.; Vysyaraju, Kranthi; Negherbon, Jesse; Levetin, Estelle; Horner, W. Elliot; Hartung, Thomas; Breysse, Patrick N.
2014-01-01
Background Spores from basidiomycete fungi (basidiospores) are highly prevalent in the atmosphere of urban and rural settings. Studies have confirmed their potential to affect human health as allergens. Less is known about their potential to serve as stimuli of the innate immune system and induce pro-inflammatory reactions. Methods In this study, we evaluated the pro-inflammatory potential of spores from 11 allergenic gilled (Pleurotus ostreatus, Oudemansiella radicata, Armillaria tabescens, Coprinus micaceus, Pluteus cervinus, Chlorophyllum molybdites) and non-gilled (Pisolithus arhizus, Merulius tremullosus, Calvatia cyathiformis, Lycoperdon pyriforme, Boletus bicolor) basidiomycetes fungi based on their potency to induce the release of the pro-inflammatory cytokine interleukin (IL)-1β in a cryopreserved human whole blood system. In addition, the role of morphological features of the spores (surface area, shape, and pigmentation) were examined for their role in the spores’ interleukin (IL)-1β-including potency. Peripheral blood from healthy volunteers was collected, pooled, and cryopreserved. After stimulating the cryopreserved pooled blood with 106 to 103 basidiospores/ml, the concentration of IL-1β in culture supernatants was determined with ELISA. Results Basidiospores manifested concentration-dependent IL-1β-inducing potency, which was more noteworthy among basidiospores from gilled basidiomycetes. At higher concentrations of basidiospores, the IL-1β-inducing potency was able to be differentiated in the cryopreserved human whole blood system. Morphological features did not correlate with the IL-1β-inducing potency of the basidiospores, suggesting that non-morphological properties modulate the IL-1β-inducing potency. Conclusion Our data provides evidence of the pro-inflammatory potential of basidiospores, and the utility of cryopreserved human whole blood as a human-based in-vitro system to study the immune reactivity of allergenic basidiospores. PMID:24356469
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Brown, Iain; Cascio, Maria G.; Wahle, Klaus W.J.; Smoum, Reem; Mechoulam, Raphael; Ross, Ruth A.; Pertwee, Roger G.; Heys, Steven D.
2010-01-01
The omega-3 fatty acid ethanolamides, docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA), displayed greater anti-proliferative potency than their parent omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in LNCaP and PC3 prostate cancer cells. DHEA and EPEA activated cannabinoid CB1 and CB2 receptors in vitro with significant potency, suggesting that they are endocannabinoids. Both LNCaP and PC3 cells expressed CB1 and CB2 receptors, and the CB1- and CB2-selective antagonists, AM281 and AM630, administered separately or together, reduced the anti-proliferative potencies of EPEA and EPA but not of DHEA or DHA in PC3 cells and of EPA but not of EPEA, DHEA or DHA in LNCaP cells. Even so, EPEA and EPA may not have inhibited PC3 or LNCaP cell proliferation via cannabinoid receptors since the anti-proliferative potency of EPEA was well below the potency it displayed as a CB1 or CB2 receptor agonist. Indeed, these receptors may mediate a protective effect because the anti-proliferative potency of DHEA in LNCaP and PC3 cells was increased by separate or combined administration of AM281 and AM630. The anandamide-metabolizing enzyme, fatty acid amide hydrolase (FAAH), was highly expressed in LNCaP but not PC3 cells. Evidence was obtained that FAAH metabolizes EPEA and DHEA and that the anti-proliferative potencies of these ethanolamides in LNCaP cells can be enhanced by inhibiting this enzyme. Our findings suggest that the expression of cannabinoid receptors and of FAAH in some tumour cells could well influence the effectiveness of DHA and EPA or their ethanolamide derivatives as anticancer agents. PMID:20660502
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Saxena, K; Lalezari, S; Oldenburg, J; Tseneklidou-Stoeter, D; Beckmann, H; Yoon, M; Maas Enriquez, M
2016-09-01
BAY 81-8973 (Kovaltry(®) ) is a full-length, unmodified recombinant human factor VIII (FVIII) with the same amino acid sequence as sucrose-formulated recombinant FVIII and is produced using additional advanced manufacturing technologies. To demonstrate efficacy and safety of BAY 81-8973 for treatment of bleeds and as prophylaxis based on two different potency assignments. In LEOPOLD I (ClinicalTrials.gov identifier, NCT01029340), males aged 12-65 years with severe haemophilia A and ≥150 exposure days received BAY 81-8973 20-50 IU kg(-1) two or three times per week for 12 months. Potency was based on chromogenic substrate assay per European Pharmacopoeia and label adjusted to mimic one-stage assay potency. Patients were randomized for potency sequence and crossed over potency groups after 6 months, followed by an optional 12-month extension. Primary efficacy endpoint was annualized bleeding rate (ABR). Patients also received BAY 81-8973 during major surgeries. Sixty-two patients received BAY 81-8973 prophylaxis and were included in the analysis. Median ABR was 1.0 (quartile 1, 0; quartile 3, 5.1) without clinically relevant differences between potency periods. Median ABR was similar for twice-weekly vs. three times-weekly dosing (1.0 vs. 2.0). Haemostasis was maintained during 12 major surgeries. Treatment-related adverse event (AE) incidence was ≤7% overall; no patient developed inhibitors. One patient with risk factors for cardiovascular disease developed a myocardial infarction. BAY 81-8973 was efficacious in preventing and treating bleeding episodes, irrespective of the potency assignment method, with few treatment-related AEs. Caution should be used when treating older patients with cardiovascular risk factors. © 2016 Bayer. Haemophilia Published by John Wiley & Sons Ltd.
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Yahara, I; Yamagata, H; Ueno, M; Inoue, S; Sato, K; Nishimura, K; Miyauchi, H; Hirata, M; Muraoka, Y; Kimura, Y; Kitamura, T; Kato, I
2001-05-01
One- or three-month repeated oral dose toxicity studies of Cefmatilen hydrochloride hydrate (S-1090) were conducted in beagle dogs. Doses were set at 25, 100 and 400 mg potency/kg/day in both studies. In both studies, no deaths occurred, and reddish-brown feces (due to chelated products of S-1090 and its decomposition products with Fe3+ in the diet) were observed in all treated groups. A transient excretion of reddish urine was observed in the 400 mg potency/kg group and a slight increase in plasma irons was also observed in the 100 and 400 mg potency/kg groups of both studies. However, as no changes suggesting anemia or hepatic injury were noted in these groups, the change of plasma irons was considered to have no toxicological significance. Plasma S-1090 concentrations increased in a manner less than dose-proportional in both studies. In the one-month toxicity study, no toxicologically significant changes, including the above findings, were noted, so the NOAEL was assessed to be 400 mg potency/kg/day. In the three-month toxicity study, urinalysis in the 400 mg potency/kg group revealed a positive reaction to occult blood and erythrocytes in sediments. In the pathological examinations, submucosal edema, hemorrhage, inflammatory cell infiltration and occasionally focal mucosal thickening were observed in the urinary bladder of the 400 mg potency/kg group. The cystisis was considered to result from chronic stimulation with the metabolite(s) of S-1090 in urine, and the reversibility was demonstrable upon one-month drug withdrawal. From these results, the NOAEL of S-1090 in the three-month toxicity study was assessed to be 100 mg potency/kg/day.
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Faurschou, Annesofie; Wulf, Hans C
2008-05-01
To examine the effect of topical corticosteroid treatment on acute sunburn. Randomized, double-blind clinical trial. University dermatology department. Twenty healthy volunteers with Fitzpatrick skin types I (highly sensitive, always burns easily, tans minimally) through III (sun-sensitive skin, sometimes burns, slowly tans to light brown). Seven 34-cm(2) areas were marked on the upper aspect of the back of each participant. An untreated area was tested to determine UV sensitivity. Two areas were treated with excess amounts (2 mg/cm(2)) of either a moderate-potency corticosteroid or a high-potency corticosteroid 30 minutes before UV-B exposure as controls. Six or 23 hours after exposure to radiation, the remaining areas were treated with the 2 corticosteroid preparations. The sunburn improvement factor (SIF) was determined by the following equation: SIF = MED (minimal erythema dose) on treated skin/MED on nontreated skin. An SIF greater than 1 indicated an effect of topical corticosteroids in sunburn relief. The SIFs in the areas treated with either topical corticosteroid 30 minutes before UV-B exposure or high-potency corticosteroid 6 hours after UV-B exposure were significantly different from SIFs in areas that received no treatment (SIF 1.1-1.7; P < .05). Only the median SIF of 1.7 in the areas treated with high-potency corticosteroid 30 minutes before UV-B exposure was clinically relevant. The areas treated 23 hours after UV-B exposure and the areas treated with a moderate-potency corticosteroid 6 hours after UV-B exposure showed no significant reduction in redness. Treatment with topical moderate-potency or high-potency corticosteroids does not provide a clinically useful decrease in the acute sunburn reaction when applied 6 or 23 hours after UV exposure.
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Potency assay design for adjuvanted recombinant proteins as malaria vaccines.
Giersing, Birgitte K; Dubovsky, Filip; Saul, Allan; Denamur, Francoise; Minor, Philip; Meade, Bruce
2006-05-15
Many licensed vaccines are composed of live, attenuated or inactivated whole-cell microorganisms, or they comprise purified components from whole-cell extracts or culture supernatants. For some diseases, pathology is fairly well understood, and there may be known correlates of protection that provide obvious parameters for assessment of vaccine potency. However, this is not always the case, and some effective vaccines are routinely used even though the mechanisms or correlates of protection are unknown. Some more modern vaccine approaches employ purified recombinant proteins, based on molecules that appear on the surface of the pathogen. This is one of the strategies that has been adopted in the quest to develop a malaria vaccine. Use of these parasite antigens as vaccine candidates is supported by substantial epidemiological data, and some have demonstrated the ability to elicit protective responses in animal models of malaria infection. However, there is as yet no immunological correlate of protection and no functional assays or animal models that have demonstrated the ability to predict efficacy in humans. There is little precedence for the most appropriate and practical method for assessing potency of vaccines based on these recombinant molecules for malaria vaccines. This is likely because the majority of malaria vaccine candidates have only recently entered clinical evaluation. The PATH Malaria Vaccine Initiative (MVI) convened a panel with expertise in potency assay design from industry, governmental institutions, and regulatory bodies to discuss and review the rationale, available methods, and best approaches for assessing the potency of recombinant proteins, specifically for their use as malarial vaccines. The aim of this meeting was to produce a discussion document on the practical potency assessment of recombinant protein malaria vaccines, focusing on early phase potency assay development.
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Plattner, Sabine; Erb, Robert; Chervet, Jean-Pierre; Oberacher, Herbert
2014-01-01
In this proof-of-principle study, the applicability of electrospray ionization-mass spectrometry (ESI-MS) to characterize the reducing potencies of natural antioxidants is demonstrated. The ESI source represents a controlled-current electrochemical cell. The interfacial potential at the emitter electrode will be at or near the electrochemical potential of those reactions that sufficiently supply all the required current for the ESI circuit. Indicator molecules prone to oxidation in ESI such as amodiaquine were used to visualize the impact of reducing compounds on the interfacial potential. The extent of inhibition of the oxidation of the indicator molecule was found to be dependent on the kind and amount of antioxidant added. Concentration-inhibition curves were constructed and used to compare reducing potencies and to rank antioxidants. This ranking was found to be dependent on the electrode material-indicator molecule combination applied. For fast and automated characterization of the reducing potencies of electrochemically active molecules, a flow-injection system was combined with ESI-MS. Liquid chromatography was used to process complex biological samples, such as red and white wine. Due to their high content of different polyphenols, red wine fractions were found to exhibit higher reducing potencies than the corresponding white wine fractions. Furthermore, for 14 important natural antioxidants, the results obtained with the controlled-current EC-ESI-MS assay were compared to those obtained with chemical antioxidant assays. Irrespectively of the kind of assay used to test the reducing potency, gallic acid, quercetin, and epicatechin were found to be potent reductants. Other antioxidants performed well in one particular assay only. This observation suggests that different kinds of redox and antioxidant chemistry were assessed with each of the assays applied. Therefore, several assays should be used to comprehensively study antioxidants and their reducing potencies.
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Assessment of toxic potency of complex mixtures of PAHs from Lincoln Creek, Milwaukee, WI
DOE Office of Scientific and Technical Information (OSTI.GOV)
Villeneuve, D.; Crunkilton, R.; DeVita, W.
1995-12-31
An assay of cytochrome P4501A catalytic activity in PLHC-1 fish hepatoma cells was used to evaluate the toxic potency of dialysates from triolein filled semipermeable polymeric membrane devices (SPMDS) exposed for variable durations and under various flow regimes to water from Lincoln Creek. Toxic potency was expressed as 2,3,7,8 tetrachlorodibenzo-p-dioxin equivalents (TCDD-EQ) calculated from bioassay results. Dose-dependent responses in measured ethoxyresorufin-o-deethylase (EROD) activity of PLHC-1 cells exposed to SPMD dialysates were shown. Toxic potency of dialysates, expressed as bioassay derived TCDD equivalents, increased with duration of SPMD exposure in Lincoln Creek from 2.0 pg/uL for a 2 day exposure tomore » 19.5 pg/uL for a 30 day exposure. This corresponded to an increase in dialysate polycyclic aromatic hydrocarbon (PAH) concentration from 8.82 ug/g after a 2 day exposure to 24.14 ug/g after 30 days. Dialysates from SPMDs exposed to Lincoln Creek stormflow had higher toxic potencies and total PAH concentrations than those exposed to baseflow only, These results suggest that levels of PAH contamination, particularly those associated with stormflow, in Lincoln Creek have potential to accumulate in fish to levels significant enough to elicit a measurable biological response (cytochrome P4501 A induction) at a potency level approaching 0.08% that of TCDD.« less
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Kamelia, Lenny; Louisse, Jochem; de Haan, Laura; Rietjens, Ivonne M C M; Boogaard, Peter J
2017-10-01
Prenatal developmental toxicity (PDT) as observed with some petroleum substances (PS) has been associated with the presence of 3-7 ring polycyclic aromatic hydrocarbons (PAHs). In the present study, the applicability of ES-D3 cell differentiation assay of the EST to evaluate in vitro embryotoxicity potencies of PS and gas-to-liquid (GTL) products as compared to their in vivo potencies was investigated. DMSO-extracts of a range of PS, containing different amounts of PAHs, and GTL-products, which are devoid of PAHs, were tested in the ES-D3 cell proliferation and differentiation assays of the EST. The results show that PS inhibited the differentiation of ES-D3 cells into cardiomyocytes in a concentration-dependent manner at non-cytotoxic concentrations, and that their potency was proportional to their PAH content. In contrast, as expected, GTL-products did not inhibit ES-D3 cell viability or differentiation at all. The in vitro PDT potencies were compared to published in vivo PDT studies, and a good correlation was found between in vitro and in vivo results (R 2 =0.97). To conclude, our results support the hypothesis that PAHs are the primary inducers of the PDT in PS. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Betts, Catherine J; Dearman, Rebecca J; Heylings, Jon R; Kimber, Ian; Basketter, David A
2006-09-01
There is compelling evidence that contact allergens differ substantially (by 4 or 5 orders of magnitude) with respect to their inherent skin-sensitizing potency. Relative potency can now be measured effectively using the mouse local lymph node assay (LLNA) and such data form the basis of risk assessment and risk management strategies. Such determinations also facilitate distinctions being drawn between the prevalence of skin sensitization to a particular contact allergen and inherent potency. The distinction is important because chemicals that are implicated as common causes of contact allergy are not necessarily potent sensitizers. One example is provided by nickel that is undoubtedly a common cause of allergic contact dermatitis, but is a comparatively weak sensitizer in predictive tests. In an attempt to explore other examples of contact allergens where there may exist a discrepancy between prevalence and potency, we describe here analyses conducted with methyl methacrylate (MMA). Results of LLNA studies have been interpreted in the context of historical clinical data on occupational allergic contact dermatitis associated with exposure to MMA.
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Nakajima, Nao; Kawanishi, Michiko; Imamura, Saiki; Hirano, Fumiya; Uchiyama, Mariko; Yamamoto, Kinya; Nagai, Hidetaka; Futami, Kunihiko; Katagiri, Takayuki; Maita, Masashi; Kijima, Mayumi
2014-05-01
Lactococcicosis is an infection caused by the bacterium Lactococcus garvieae and creates serious economic damage to cultured marine and fresh water fish industries. The use of the assay currently applied to evaluate the potency of the lactococcicosis vaccine is contingent upon meeting specific parameters after statistical analysis of the percent survival of the vaccinated yellowtail or greater amberjack fish after challenge with a virulent strain of L. garvieae. We found that measuring the serological response with a quantitative agglutinating antibody against the L. garvieae antigen (phenotype KG+) was an effective method of monitoring the potency of lactococcicosis vaccines. Vaccinated fish had significantly higher antibody titers than control fish when the L. garvieae Lg2-S strain was used as an antigen. Furthermore, the titer of the KG + agglutinating antibody was correlated with vaccine potency, and the cut-off titer was determined by comparing the data with those from the challenge test. An advantage of the proposed serology-based potency assay is that it will contribute to reduced numbers of animal deaths during vaccine potency evaluations. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Work-group characteristics and performance in collectivistic and individualistic cultures.
Sosik, John J; Jung, Dong I
2002-02-01
The authors conducted a cross-cultural longitudinal investigation of the effects of culture (individualism-collectivism dichotomy) on group characteristics (functional heterogeneity, preference for teamwork, group potency, outcome expectation) and on performance of 83 work groups performing 2 decision-making tasks over a 15-week period. The individualists (U.S. students) reported higher levels of functional heterogeneity and group potency and attained higher levels of group performance than did the collectivists (Korean students). In addition, culture and time interacted to influence ratings of group potency and outcome expectation. The difference in ratings of group potency between individualists and collectivists increased over time. Outcome expectation was greater among the collectivists in Time 1 and among the individualists in Time 2. The authors discuss implications for future cross-cultural group research and international management.
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Seewald, Jeffrey S.; Seyfried, W.E.; Shanks, Wayne C.
1994-01-01
Organic-rich diatomaceous ooze was reacted with seawater and a Na-Ca-K-Cl fluid of seawater chlorinity at 325-400??C, 400-500 bars, and fluid/sediment mass ratios of 1.56-2.35 to constrain factors regulating the abundance and stable isotope composition of C and S species during hydrothermal alteration of sediment from Guaymas Basin, Gulf of California. Alteration of inorganic and organic sedimentary components resulted in extensive exchange reactions, the release of abundant H2S, CO2, CH4, and Corganic, to solution, and recrystallization of the sediment to an assemblage containing albitic plagioclase, quartz, pyrrhotite, and calcite. The ??34Scdt values of dissolved H2S varied from -10.9 to +4.3??? during seawater-sediment interaction at 325 and 400??C and from -16.5 to -9.0??? during Na-Ca-K-Cl fluid-sediment interaction at 325 and 375??C. In the absence of seawater SO4, H2S is derived from both the transformation of pyrite to pyrrhotite and S released during the degradation of organic matter. In the presence of seawater SO4, reduction of SO4 contributes directly to H2S production. Sedimentary organic matter acts as the reducing agent during pyrite and SO4 reduction. Requisite acidity for the reduction of SO4 is provided by Mg fixation during early-stage sediment alteration and by albite and calcite formation in Mg-free solutions. Organically derived CH4 was characterized by ??13Cpdb values ranging between -20.8 and -23.1???, whereas ??13Cpdb values for dissolved Corganic ranged between -14.8 and -17.7%. Mass balance calculations indicate that ??13C values for organically derived CO2 were ??? - 14.8%. Residual solid sedimentary organic C showed small (??? 0.7???) depletions in 13C relative to the starting sediment. The experimental results are consistent with the isotopic and chemical composition of natural hydrothermal fluids and minerals at Guaymas Basin and permit us to better constrain sources and sinks for C and S species in subseafloor hydrothermal systems at sediment-covered spreading centers. Our data show that the sulfur isotope composition of hydrothermal Sulfide minerals in Guaymas Basin can be explained by derivation of S from diagenetic sulfide and seawater sulfate. Basaltic S may also contribute to hydrothermal sulfide precipitates but is not required to explain their isotopic composition. Estimates of seawater/ sediment mass ratios based on sulfur isotopic composition of sulfide minerals and the abundance of dissolved NH3 in vent fluids range from 3-29 during hydrothermal circulation. Sources of C in Guaymas Basin hydrothermal fluids include thermal degradation of organic matter, bacteriogenic methane production, and dissolution of diagenetic carbonate. ?? 1994.
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Wolf, P A; Bridges, J R; Wicklund, R
2010-03-01
The agonist-receptor-transducer model of D. Ennis is applied to beverage formulations sweetened with high fructose corn syrup, sucralose, and other high-potency sweeteners, confirming the utility of the model, and supports the growing volume of evidence for multiple binding sites on the sweetness receptor. The model is further simplified to require less parameters for other sweetener blend systems whenever potency information is available for the single sweeteners.
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The spermicidal potency of Coca-Cola and Pepsi-Cola.
Hong, C Y; Shieh, C C; Wu, P; Chiang, B N
1987-09-01
The inhibitory effect of Old Coke, caffeine-free New Coke, New Coke, Diet Coke and Pepsi-Cola on human sperm motility was studied with a trans-membrane migration method. None of them could decrease sperm motility to less than 70% of control within one hour. A previous study which claimed a marked variation of spermicidal potencies among different formulations of Coca-Cola could not be confirmed. Even if cola has a spermicidal effect, its potency is relatively weak as compared with other well-known spermicidal agents.
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Clapp, Tanya; Munks, Michael W; Trivedi, Ruchit; Kompella, Uday B; Braun, LaToya Jones
2014-06-24
Preventing losses in vaccine potency due to accidental freezing has recently become a topic of interest for improving vaccines. All vaccines with aluminum-containing adjuvants are susceptible to such potency losses. Recent studies have described excipients that protect the antigen from freeze-induced inactivation, prevent adjuvant agglomeration and retain potency. Although these strategies have demonstrated success, they do not provide a mechanistic understanding of freeze-thaw (FT) induced potency losses. In the current study, we investigated how adjuvant frozen in the absence of antigen affects vaccine immunogenicity and whether preventing damage to the freeze-sensitive recombinant hepatitis B surface antigen (rHBsAg) was sufficient for maintaining vaccine potency. The final vaccine formulation or Alhydrogel(®) alone was subjected to three FT-cycles. The vaccines were characterized for antigen adsorption, rHBsAg tertiary structure, particle size and charge, adjuvant elemental content and in-vivo potency. Particle agglomeration of either vaccine particles or adjuvant was observed following FT-stress. In vivo studies demonstrated no statistical differences in IgG responses between vaccines with FT-stressed adjuvant and no adjuvant. Adsorption of rHBsAg was achieved; regardless of adjuvant treatment, suggesting that the similar responses were not due to soluble antigen in the frozen adjuvant-containing formulations. All vaccines with adjuvant, including the non-frozen controls, yielded similar, blue-shifted fluorescence emission spectra. Immune response differences could not be traced to differences in the tertiary structure of the antigen in the formulations. Zeta potential measurements and elemental content analyses suggest that FT-stress resulted in a significant chemical alteration of the adjuvant surface. This data provides evidence that protecting a freeze-labile antigen from subzero exposure is insufficient to maintain vaccine potency. Future studies should focus on adjuvant protection. To our knowledge, this is the first study to systematically investigate how FT-stress to adjuvant alone affects immunogenicity. It provides definitive evidence that this damage is sufficient to reduce vaccine potency. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Männikkö, R; Overend, G; Perrey, C; Gavaghan, CL; Valentin, J-P; Morten, J; Armstrong, M; Pollard, CE
2010-01-01
Background and purpose: Potencies of compounds blocking KV11.1 [human ether-ago-go-related gene (hERG)] are commonly assessed using cell lines expressing the Caucasian wild-type (WT) variant. Here we tested whether such potencies would be different for hERG single nucleotide polymorphisms (SNPs). Experimental approach: SNPs (R176W, R181Q, Del187-189, P347S, K897T, A915V, P917L, R1047L, A1116V) and a binding-site mutant (Y652A) were expressed in Tet-On CHO-K1 cells. Potencies [mean IC50; lower/upper 95% confidence limit (CL)] of 48 hERG blockers was estimated by automated electrophysiology [IonWorks™ HT (IW)]. In phase one, rapid potency comparison of each WT-SNP combination was made for each compound. In phase two, any compound-SNP combinations from phase one where the WT upper/lower CL did not overlap with those of the SNPs were re-examined. Electrophysiological WT and SNP parameters were determined using conventional electrophysiology. Key results: IW detected the expected sixfold potency decrease for propafenone in Y652A. In phase one, the WT lower/upper CL did not overlap with those of the SNPs for 77 compound-SNP combinations. In phase two, 62/77 cases no longer yielded IC50 values with non-overlapping CLs. For seven of the remaining 15 cases, there were non-overlapping CLs but in the opposite direction. For the eight compound-SNP combinations with non-overlapping CLs in the same direction as for phase 1, potencies were never more than twofold apart. The only statistically significant electrophysiological difference was the voltage dependence of activation of R1047L. Conclusion and implications: Potencies of hERG channel blockers defined using the Caucasian WT sequence, in this in vitro assay, were representative of potencies for common SNPs. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 PMID:19673885
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Thongtang, Nuntakorn; Lin, Jianxin; Schaefer, Ernst J.; Lowe, Robert S.; Tomassini, Joanne E.; Shah, Arvind K.; Tershakovec, Andrew M.
2013-01-01
Objective Statins inhibit cholesterol synthesis but can upregulate cholesterol absorption, with higher doses producing larger effects. Ezetimibe inhibits cholesterol absorption but also upregulates synthesis. We tested whether ezetimibe added to ongoing statin therapy would be most effective in lowering LDL-cholesterol (LDL-C) in subjects on high-potency statins and whether these effects would be related to alterations in cholesterol absorption (β-sitosterol) and synthesis (lathosterol) markers. Methods Hypercholesterolemic subjects (n=874) on statins received ezetimibe 10 mg/day. Plasma lipids, lathosterol, and β-sitosterol were measured at baseline and on treatment. Subjects were divided into low- (n=133), medium- (n=582), and high- (n=159) statin potency groups defined by predicted LDL-C–lowering effects of each ongoing statin type and dose (reductions of ~20-30%, ~31-45%, or ~46-55%, respectively). Results The high-potency group had significantly lower baseline lathosterol (1.93 vs. 2.58 vs. 3.17 μmol/l; p <0.001) and higher baseline β-sitosterol values (6.21 vs. 4.58 vs. 4.51 μmol/l, p <0.001) than medium-/low-potency groups. Ezetimibe treatment in the high-potency group produced significantly greater reductions from baseline in LDL-C than medium-/low-potency groups (−29.1% vs. −25.0% vs. −22.7%; p <0.001) when evaluating unadjusted data. These effects and group differences were significantly (p <0.05) related to greater β-sitosterol reductions and smaller lathosterol increases. However, LDL-C reduction differences between groups were no longer significant after controlling for placebo effects, due mainly to modest LDL-C lowering by placebo in the high-potency group. Conclusion Patients on high-potency statins have the lowest levels of cholesterol synthesis markers and the highest levels of cholesterol absorption markers at baseline, and the greatest reduction in absorption markers and the smallest increases in synthesis markers with ezetimibe addition. Therefore, such patients may be good candidates for ezetimibe therapy if additional LDL-C lowering is needed. PMID:23040830
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Ayoub, Daniel; Jabs, Wolfgang; Resemann, Anja; Evers, Waltraud; Evans, Catherine; Main, Laura; Baessmann, Carsten; Wagner-Rousset, Elsa; Suckau, Detlev; Beck, Alain
2013-01-01
The European Medicines Agency received recently the first marketing authorization application for a biosimilar monoclonal antibody (mAb) and adopted the final guidelines on biosimilar mAbs and Fc-fusion proteins. The agency requires high similarity between biosimilar and reference products for approval. Specifically, the amino acid sequences must be identical. The glycosylation pattern of the antibody is also often considered to be a very important quality attribute due to its strong effect on quality, safety, immunogenicity, pharmacokinetics and potency. Here, we describe a case study of cetuximab, which has been marketed since 2004. Biosimilar versions of the product are now in the pipelines of numerous therapeutic antibody biosimilar developers. We applied a combination of intact, middle-down, middle-up and bottom-up electrospray ionization and matrix assisted laser desorption ionization mass spectrometry techniques to characterize the amino acid sequence and major post-translational modifications of the marketed cetuximab product, with special emphasis on glycosylation. Our results revealed a sequence error in the reported sequence of the light chain in databases and in publications, thus highlighting the potency of mass spectrometry to establish correct antibody sequences. We were also able to achieve a comprehensive identification of cetuximab's glycoforms and glycosylation profile assessment on both Fab and Fc domains. Taken together, the reported approaches and data form a solid framework for the comparability of antibodies and their biosimilar candidates that could be further applied to routine structural assessments of these and other antibody-based products.
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Patel, Mohit B; Garrad, Evan C; Stavri, Ariel; Gokel, Michael R; Negin, Saeedeh; Meisel, Joseph W; Cusumano, Zachary; Gokel, George W
2016-06-15
Hydraphiles are synthetic amphiphiles that form ion-conducting pores in liposomal membranes. These pores exhibit open-close behavior when studied by planar bilayer conductance techniques. In previous work, we showed that when co-administered with various antibiotics to the DH5α strain of Escherichia coli, they enhanced the drug's potency. We report here potency enhancements at low concentrations of hydraphiles for the structurally and mechanistically unrelated antibiotics erythromycin, kanamycin, rifampicin, and tetracycline against Gram negative E. coli (DH5α and K-12) and Pseudomonas aeruginosa, as well as Gram positive Bacillus subtilis. Earlier work suggested that potency increases correlated to ion transport function. The data presented here comport with the function of hydraphiles to enhance membrane permeability in addition to, or instead of, their known function as ion conductors. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Suwanmanee, Siros; Buckingham, Steven David; Biggin, Philip; Sattelle, David
2014-01-01
Ionotropic GABA receptors are the targets for several classes of insecticides. One of the most widely-studied insect GABA receptors is RDL (resistance to dieldrin), originally isolated from Drosophila melanogaster. RDL undergoes alternative splicing and RNA editing, which influence the potency of GABA. Most work has focussed on minority isoforms. Here, we report the first characterisation of the predominant native splice variant and RNA edit, combining functional characterisation with molecular modelling of the agonist-binding region. The relative order of agonist potency is GABA> muscimol> TACA> β-alanine. The I/V edit does not alter the potency of GABA compared to RDLbd. Docking calculations suggest that these agonists bind and activate RDLbdI/V through a similar binding mode. TACA and β-alanine are predicted to bind with lower affinity than GABA, potentially explaining their lower potency, whereas the lower potency of muscimol and isoguvacine cannot be explained structurally from the docking calculations. The A301S (resistance to dieldrin) mutation reduced the potency of antagonists picrotoxin, fipronil and pyrafluprole but the I/V edit had no measurable effect. Ivermectin suppressed responses to GABA of RDLbdI/V, RDLbd and RDLbdI/VA301S. The dieldrin resistant variant also showed reduced sensitivity to Ivermectin. This study of a highly abundant insect GABA receptor isoform will help the design of new insecticides. PMID:24823815
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Roberts, David W; Api, Anne Marie; Safford, Robert J; Lalko, Jon F
2015-08-01
An essential step in ensuring the toxicological safety of chemicals used in consumer products is the evaluation of their skin sensitising potential. The sensitising potency, coupled with information on exposure levels, can be used in a Quantitative Risk Assessment (QRA) to determine an acceptable level of a given chemical in a given product. Where consumer skin exposure is low, a risk assessment can be conducted using the Dermal Sensitisation Threshold (DST) approach, avoiding the need to determine potency experimentally. Since skin sensitisation involves chemical reaction with skin proteins, the first step in the DST approach is to assess, on the basis of the chemical structure, whether the chemical is expected to be reactive or not. Our accompanying publication describes the probabilistic derivation of a DST of 64 μg/cm(2) for chemicals assessed as reactive. This would protect against 95% of chemicals assessed as reactive, but the remaining 5% would include chemicals with very high potency. Here we discuss the chemical properties and structural features of high potency sensitisers, and derive an approach whereby they can be identified and consequently excluded from application of the DST. Copyright © 2015 Elsevier Inc. All rights reserved.
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Li, Changgui; Xu, Kangwei; Hashem, Anwar; Shao, Ming; Liu, Shuzhen; Zou, Yong; Gao, Qiang; Zhang, Yongchao; Yuan, Liyong; Xu, Miao; Li, Xuguang; Wang, Junzhi
2015-01-01
The outbreak of human infections of a novel avian influenza virus A (H7N9) prompted the development of the vaccines against this virus. Like all types of influenza vaccines, H7N9 vaccine must be tested for its potency prior to being used in humans. However, the unavailability of international reference reagents for the potency determination of H7N9 vaccines substantially hinders the progress in vaccine development. To facilitate clinical development, we enlisted 5 participants in a collaborative study to develop critical reagents used in Single Radial Immunodiffusion (SRID), the currently acceptable assay for potency determination of influenza vaccine. Specifically, the hemagglutinin (HA) content of one vaccine bulk for influenza A (H7N9), herein designated as Primary Liquid Standard (PLS), was determined by SDS-PAGE. In addition, the freeze-dried antigen references derived from PLS were prepared to enhance the stability for long term storage. The final HA content of lyophilized antigen references were calibrated against PLS by SRID assay in a collaborative study. Importantly, application of these national reference standards to potency analyses greatly facilitated the development of H7N9 vaccines in China. PMID:25970793
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Ozaki, Y
1990-02-01
Vasodilative effects of hirsutine (HS) and hirsuteine (HST) which were isolated from the domestic plant Uncaria rhynchophylla Miq. and beta-yohimbine (beta-Y) which was isolated from the domestic plant Amsonia elliptica Roem. et Schult. were carried out. In the hind-limb artery of anesthetized dogs, intra-arterial administration of HS, HST and beta-Y caused a vasodilatation. The vasodilative potency of HS was somewhat stronger than that of HST, and the potency of both alkaloids was approximately equal to that of papaverine. The vasodilative effect of beta-Y was similar to that of yohimbine, which is considered to be derived from its alpha-adrenoceptor blocking effect, and the potency of both alkaloids was approximately the same, while the effect of beta-Y was stronger than that of papaverine. In the coronary artery, HS showed a vasodilatation and its potency was weaker than that of papaverine. Also, HS showed the same effect in the cerebral artery, and the potency of HS was approximately the same as that of papaverine. These results suggest that the mode of the vasodilative effect induced by HS may partly differ from that of papaverine.
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Ren, Ji-Xia; Li, Lin-Li; Zheng, Ren-Lin; Xie, Huan-Zhang; Cao, Zhi-Xing; Feng, Shan; Pan, You-Li; Chen, Xin; Wei, Yu-Quan; Yang, Sheng-Yong
2011-06-27
In this investigation, we describe the discovery of novel potent Pim-1 inhibitors by employing a proposed hierarchical multistage virtual screening (VS) approach, which is based on support vector machine-based (SVM-based VS or SB-VS), pharmacophore-based VS (PB-VS), and docking-based VS (DB-VS) methods. In this approach, the three VS methods are applied in an increasing order of complexity so that the first filter (SB-VS) is fast and simple, while successive ones (PB-VS and DB-VS) are more time-consuming but are applied only to a small subset of the entire database. Evaluation of this approach indicates that it can be used to screen a large chemical library rapidly with a high hit rate and a high enrichment factor. This approach was then applied to screen several large chemical libraries, including PubChem, Specs, and Enamine as well as an in-house database. From the final hits, 47 compounds were selected for further in vitro Pim-1 inhibitory assay, and 15 compounds show nanomolar level or low micromolar inhibition potency against Pim-1. In particular, four of them were found to have new scaffolds which have potential for the chemical development of Pim-1 inhibitors.
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Identification of Transthyretin Fibril Formation Inhibitors Using Structure-Based Virtual Screening.
Ortore, Gabriella; Martinelli, Adriano
2017-08-22
Transthyretin (TTR) is the primary carrier for thyroxine (T 4 ) in cerebrospinal fluid and a secondary carrier in blood. TTR is a stable homotetramer, but certain factors, genetic or environmental, could promote its degradation to form amyloid fibrils. A docking study using crystal structures of wild-type TTR was planned; our aim was to design new ligands that are able to inhibit TTR fibril formation. The computational protocol was thought to overcome the multiple binding modes of the ligands induced by the peculiarity of the TTR binding site and by the pseudosymmetry of the site pockets, which generally weaken such structure-based studies. Two docking steps, one that is very fast and a subsequent step that is more accurate, were used to screen the Aldrich Market Select database. Five compounds were selected, and their activity toward inhibiting TTR fibril formation was assessed. Three compounds were observed to be actives, two of which have the same potency as the positive control, and the other was found to be a promising lead compound. These results validate a computational protocol that is able to archive information on the key interactions between database compounds and TTR, which is valuable for supporting further studies. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Rayan, P; Matthews, B; McDonnell, P A; Cock, I E
2015-07-01
Giardisis is a debilitating disease caused by gastrointestinal parasites of the genus Giardia. High-antioxidant T. ferdinandiana fruit extracts were investigated for the ability to block Giardia duodenalis growth. Methanolic and aqueous extracts had the most potent growth inhibitory activity (IC50 values of approximately 700 and 140 μg/ml, respectively). Ethyl acetate and chloroform extracts also inhibited G. duodenalis growth, albeit with lower potency. The hexane extract was completely devoid of G. duodenalis growth inhibitory activity. All extracts were nontoxic in the Artemia fransiscana bioassay. Nontargeted HPLC-quadrupole time-of-flight (QTOF) mass spectroscopy (with screening against three compound databases) putatively identified 17 compounds in all of the inhibitory extracts but not in the inactive hexane extract. The low toxicity of the Terminalia ferdinandiana fruit extracts and their potent G. duodenalis growth inhibitory bioactivity indicate their potential as medicinal agents in the treatment and prevention of this disease.
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Pineda, Sandy S; Chaumeil, Pierre-Alain; Kunert, Anne; Kaas, Quentin; Thang, Mike W C; Le, Lien; Nuhn, Michael; Herzig, Volker; Saez, Natalie J; Cristofori-Armstrong, Ben; Anangi, Raveendra; Senff, Sebastian; Gorse, Dominique; King, Glenn F
2018-03-15
ArachnoServer is a manually curated database that consolidates information on the sequence, structure, function and pharmacology of spider-venom toxins. Although spider venoms are complex chemical arsenals, the primary constituents are small disulfide-bridged peptides that target neuronal ion channels and receptors. Due to their high potency and selectivity, these peptides have been developed as pharmacological tools, bioinsecticides and drug leads. A new version of ArachnoServer (v3.0) has been developed that includes a bioinformatics pipeline for automated detection and analysis of peptide toxin transcripts in assembled venom-gland transcriptomes. ArachnoServer v3.0 was updated with the latest sequence, structure and functional data, the search-by-mass feature has been enhanced, and toxin cards provide additional information about each mature toxin. http://arachnoserver.org. support@arachnoserver.org. Supplementary data are available at Bioinformatics online.
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Rationale for Further Medical and Health Research on High-Potency Sweeteners
2012-01-01
High-potency or artificial sweeteners have historically been considered inert compounds without physiological consequences other than taste sensations. However, recent data suggest that some of these sweeteners have biological effects that may impact human health. Furthermore, there are significant gaps in our current knowledge of the pharmacokinetics of these sweeteners, their potential for “sweetener–drug interactions” and their impact on appetite and body weight regulation. Nine research needs are described that address some of the major unknown issues associated with ingestion of high-potency sweeteners. PMID:22539626
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Rationale for further medical and health research on high-potency sweeteners.
Schiffman, Susan S
2012-10-01
High-potency or artificial sweeteners have historically been considered inert compounds without physiological consequences other than taste sensations. However, recent data suggest that some of these sweeteners have biological effects that may impact human health. Furthermore, there are significant gaps in our current knowledge of the pharmacokinetics of these sweeteners, their potential for "sweetener-drug interactions" and their impact on appetite and body weight regulation. Nine research needs are described that address some of the major unknown issues associated with ingestion of high-potency sweeteners.
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Evaluation of the potential carcinogenicity of benzotrichloride (97-07-7). Final report
DOE Office of Scientific and Technical Information (OSTI.GOV)
Not Available
1988-06-01
Benzotrichloride is a probable human carcinogen, classified as weight-of-evidence Group B1 under the EPA Guidelines for Carcinogen Risk Assessment. Evidence on potential carcinogenicity from animal studies is Sufficient, and the evidence from human studies is Limited. The potency factor (F) for benzotrichloride is estimated to be 58.0 (mg/kg/day)(-1), placing it in potency group 2 according to the CAG's methodology for evaluating potential carcinogens. Combining the weight-of-evidence group and the potency group, benzotrichloride is assigned a MEDIUM hazard ranking.
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Murphy, David L; Lebin, Jacob A; Severtson, Stevan G; Olsen, Heather A; Dasgupta, Nabarun; Dart, Richard C
2018-03-26
The epidemic of prescription opioid overdose and mortality parallels the dispensing rates of prescription opioids, and the availability of increasingly potent opioid analgesics. The common assumption that more potent opioid analgesics are associated with higher rates of adverse outcomes has not been adequately substantiated. We compared the rate of serious adverse events among commonly prescribed opioid analgesics of varying potency. Serious adverse events (SAEs; defined as death, major medical effect, or hospitalization) resulting from exposure to tablets containing seven opioid analgesics (oxycodone, hydrocodone, morphine, hydromorphone, oxymorphone, tapentadol, and tramadol) captured by the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS ® ) System Poison Center Program were evaluated from 2010 through 2016. Rates of SAEs were adjusted for availability through outpatient dispensing data and regressed on morphine milligram equivalents (MME). There were 19,480 cases of SAE during the 7-year study period. Hydrocodone and oxycodone contributed to 77% of SAE cases. Comparing rates of outcome by relative potency, a hierarchy was observed with hydromorphone (8.02 SAEs/100 kg) and tapentadol (0.27 SAE/100 kg) as the highest and lowest rates, reflecting a 30-fold difference among individual opioid products. SAE rate and potency were related linearly-SAEs increased 2.04 per 100 kg drug dispensed for each 1-unit rise in MME (p = 0.004). Linear regression of SAE/100 kg drug dispensed and drug potency identified that MME comprised 96% of the variation observed. In contrast, potency did not explain variation seen using other study denominators (prescriptions dispensed, dosage units dispensed, and the number of individuals filling a prescription). Potency of a prescription opioid analgesic demonstrates a significant, highly positive linear relationship with exposures resulting in SAEs per 100 kg drug dispensed reported to poison centers. Potency should be carefully considered from both individual provider and public health perspectives.
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Box, Geoffrey N; Kaplan, Adam G; Rodriguez, Esequiel; Skarecky, Douglas W; Osann, Kathryn E; Finley, David S; Ahlering, Thomas E
2010-01-01
Whether or not sacrificing accessory pudendal arteries (APAs) during radical prostatectomy affects potency has been an ongoing source of concern. Herein, we present our potency results relative to sacrificing APAs in normally pre-potent men following robot-assisted radical prostatectomy (RARP). The distribution of APAs and clinical characteristics were prospectively recorded in 200 consecutive patients undergoing RARP with a cautery-free technique. Sexual function was assessed using the International Index of Erectile Function 5-item questionnaire (IIEF-5). All APAs were sacrificed due to stapling the dorsal vein complex. Postoperatively, potency was defined by an affirmative answer to the following two questions: "Were erections adequate for penetration?" and "were the erections satisfactory?" Postoperative IIEF-5 scores and quality of erections (% of preoperative firmness: 0%, 25%, 50%, 75%, 100%) were also obtained. Subgroup analysis of patients age < or =65 years with IIEF-5 score of 22-25 was performed. Eighty patients (40%) had APAs. Preoperatively, there was no association with having an APA and normal/abnormal sexual function. Preoperatively, 58/200 were < or =65 years with self-administered IIEF-5 scores of 22-25. Postoperatively, 53/58 (91%) were potent at 24 months follow-up. Nineteen of 58 patients had a sacrificed APA; 39 patients had no APA. Eighteen of 19 (95%) patients with sacrificed APAs were potent vs. 35/39 (90%) with no APA present (P = 0.53). Multivariate analysis showed no significant correlation between sacrificing an APA and time of potency recovery, quality of postoperative erections (94% vs. 90% P = 0.80) or mean IIEF-5 score (22.4 vs. 20.8, P = 0.13). We found no correlation between the presence or absence of APAs and preoperative sexual function. Furthermore, after sacrificing all APAs, we found no correlation with potency return, time to return of potency, quality of erections, or mean IIEF-5 scores at 24 months.
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Shikanov, Sergey; Desai, Vikas; Razmaria, Aria; Zagaja, Gregory P; Shalhav, Arieh L
2010-05-01
We assessed the probability of achieving continence and potency after robotic radical prostatectomy in elderly patients. The cohort included 1,436 robotic radical prostatectomy cases performed at our institution between 2003 and 2008. Continence (pad-free) and potency (erection sufficient for intercourse) at baseline and 1 year after surgery were evaluated by the UCLA-PCI questionnaire. Point estimates of the predicted probabilities of continence and potency for age 65, 70 and 75 years were calculated from multivariate logistic regression models adjusting for age, nerve sparing status, baseline International Prostate Symptom Score and baseline Sexual Health Inventory for Men score. Patients who were impotent before surgery or those who received hormones or radiation within 1 year after surgery were censored. Mean patient age was 60 years (range 38 to 85) with 25% older than 65 years and 77 (5%) 70 years old or older. Age (OR 0.97, p = 0.002), baseline I-PSS (OR 0.98, p = 0.02) and Sexual Health Inventory for Men scores (OR 1.02, p = 0.005) were independently associated with being pad-free. Age (OR 0.92, p <0.0001), baseline Sexual Health Inventory for Men score (OR 1.1, p <0.0001) and bilateral nerve sparing (OR 2.92, p <0.0001) were independently associated with achieving potency. Predicted probabilities (95% CI) of postoperative 1-year continence at age 65, 70 and 75 years were 0.66 (0.63, 0.69), 0.63 (0.57, 0.68) and 0.59 (0.52, 0.66), respectively. The corresponding probabilities of postoperative 1-year potency after bilateral nerve sparing were 0.66 (0.62, 0.71), 0.56 (0.49, 0.64) and 0.46 (0.36, 0.56). In our experience there is an acceptable probability of achieving continence and potency after robotic radical prostatectomy in selected elderly patients. 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
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Yi, Shou-Pu; Kong, Qing-Hong; Li, Yu-Lei; Pan, Chen-Ling; Yu, Jie; Cui, Ben-Qiang; Wang, Ying-Fei; Wang, Guan-Lin; Zhou, Pei-Lan; Wang, Li-Li; Gong, Ze-Hui; Su, Rui-Bin; Shen, Yue-Hai; Yu, Gang; Chang, Kwen-Jen
2017-07-01
Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DPI-125 and attempted to elucidate the relationship between the δ-, μ- and κ-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds (DPI-125, DPI-3290, DPI-130, KUST202 and KUST13T02) were selected for this study. PKA fluorescence redistribution assays in CHO cells individually expressing δ-, μ- or κ-receptors were used to measure the agonist potency. The respiratory safety profiles were estimated in rats by the ratio of ED 50 (pCO 2 increase)/ED 50 (antinociception). The abuse liability of DPI-125 was evaluated with a self-administration model in rhesus monkeys. The observed agonist potencies of DPI-125 for δ-, μ- and κ-opioid receptors were 4.29±0.36, 11.10±3.04, and 16.57±4.14 nmol/L, respectively. The other four compounds were also mixed agonists with varying potencies. DPI-125 exhibited a high respiratory safety profile, clearly related to its high δ-receptor potency. The ratio of the EC 50 potencies for the μ- and δ-receptors was found to be positively correlated with the respiratory safety ratio. DPI-125 has similar potencies for μ- and κ-receptors, which is likely the reason for its reduced abuse potential. Our results demonstrate that the opioid receptor mixed agonist DPI-125 is safer and less addictive than traditional μ-agonist analgesics. These findings suggest that the development of δ>μ∼κ opioid receptor mixed agonists is feasible, and such compounds could represent a promising class of potent analgesics with wider therapeutic windows.
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Thompson, Chad M; Bichteler, Anne; Rager, Julia E; Suh, Mina; Proctor, Deborah M; Haws, Laurie C; Harris, Mark A
2016-04-01
Recent analyses-highlighted by the International Workshops on Genotoxicity Testing Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment-have identified a correlation between (log) estimates of a carcinogen's in vivo genotoxic potency and in vivo carcinogenic potency in typical laboratory animal models, even when the underlying data have not been matched for tissue, species, or strain. Such a correlation could have important implications for risk assessment, including informing the mode of action (MOA) of specific carcinogens. When in vivo genotoxic potency is weak relative to carcinogenic potency, MOAs other than genotoxicity (e.g., endocrine disruption or regenerative hyperplasia) may be operational. Herein, we review recent in vivo genotoxicity and carcinogenicity data for hexavalent chromium (Cr(VI)), following oral ingestion, in relevant tissues and species in the context of the aforementioned correlation. Potency estimates were generated using benchmark doses, or no-observable-adverse-effect-levels when data were not amenable to dose-response modeling. While the ratio between log values for carcinogenic and genotoxic potency was ≥1 for many compounds, the ratios for several Cr(VI) datasets (including in target tissue) were less than unity. In fact, the ratios for Cr(VI) clustered closely with ratios for chloroform and diethanolamine, two chemicals posited to have non-genotoxic MOAs. These findings suggest that genotoxicity may not play a major role in the cancers observed in rodents following exposure to high concentrations of Cr(VI) in drinking water-a finding consistent with recent MOA and adverse outcome pathway (AOP) analyses concerning Cr(VI). This semi-quantitative analysis, therefore, may be useful to augment traditional MOA and AOP analyses. More case examples will be needed to further explore the general applicability and validity of this approach for human health risk assessment. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.
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RELATIVE POTENCY RANKING FOR CHLOROPHENOLS
Recently the National Center for Environmental Assessment-Cincinnati completed a feasibility study for developing a toxicity related relative potency ranking scheme for chlorophenols. In this study it was concluded that a large data base exists pertaining to the relative toxicity...
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Shevrin, Howard; Panksepp, Jaak; Brakel, Linda A. W.; Snodgrass, Michael
2012-01-01
Whether or not affect can be unconscious remains controversial. Research claiming to demonstrate unconscious affect fails to establish clearly unconscious stimulus conditions. The few investigations that have established unconscious conditions fail to rule out conscious affect changes. We report two studies in which unconscious stimulus conditions were met and conscious mood changes measured. The subliminal stimuli were positive and negative affect words presented at the objective detection threshold; conscious mood changes were measured with standard manikin valence, potency, and arousal scales. We found and replicated that unconscious emotional stimuli produced conscious mood changes on the potency scale but not on the valence scale. Were positive and negative affects aroused unconsciously, but reflected consciously in potency changes? Or were the valence words unconscious cognitive causes of conscious mood changes being activated without unconscious affect? A thought experiment is offered as a way to resolve this dilemma. PMID:24961258
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NASA Astrophysics Data System (ADS)
Sarah, Maya; Misran, Erni
2018-03-01
Municipal solid waste (MSW) in Medan City is facing problems either with the quantity and management of MSW. Local authority only dumped approximately 73.9% MSW in the landfill over the years. Spontaneous phenomena of methane formation in dumping site indicates the potency of MSW conversion into energy by biochemical conversion. On the contrary, the presence of plastics, woods, papers, etc. in the MSW show the potency of MSW to be treated by thermal conversion. Both thermal incineration and anaerobic digestion may convert MSW Medan City into energy. This study evaluates potency of MSW conversion into renewable energy using proximate and ultimate analysis. Overall, MSW of Medan City has the opportunities to be converted into energy by both thermal and biochemical conversion with a special requirement such as pre-dry the MSW prior incineration process and degrade organic MSW in a bioreactor.
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Stereoselective potencies and relative toxicities of coniine enantiomers.
Lee, Stephen T; Green, Benedict T; Welch, Kevin D; Pfister, James A; Panter, Kip E
2008-10-01
Coniine, one of the major toxic alkaloids present in poison hemlock ( Conium maculatum), occurs in two optically active forms. A comparison of the relative potencies of (+)- and (-)-coniine enantiomers has not been previously reported. In this study, we separated the enantiomers of coniine and determined the biological activity of each enantiomer in vitro and in vivo. The relative potencies of these enantiomers on TE-671 cells expressing human fetal nicotinic neuromuscular receptors had the rank order of (-)-coniine > (+/-)-coniine > (+)-coniine. A mouse bioassay was used to determine the relative lethalities of (-)-, (+/-)-, and (+)-coniine in vivo. The LD 50 values of the coniine enantiomers were 7.0, 7.7, and 12.1 mg/kg for the (-)-, (+/-)-, and (+)- forms of coniine, respectively. The results from this study demonstrate that there is a stereoselective difference in the in vitro potencies of the enantiomers of coniine that directly correlates with the relative toxicities of the enantiomers in vivo.
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Roles of participation and feedback in group potency.
Gamero, Nuria; Peiró, José M; Zornoza, Ana; Picazo, Carmen
2009-08-01
The roles of group participation and group performance feedback were examined as antecedents of group potency, i.e., beliefs shared among a work group's members about the general effectiveness of the work group. Also examined were how group participation and the congruence of the feedback received from different sources about performance predicted convergence in members' beliefs about group effectiveness. The sample comprised 61 work groups of professionals involved in Master in Business Administration (MBA) programs (284 participants). Mean group size was 4.6 members (SD = .58). 65% of participants were male, and 51% were between 30 and 40 years of age. Data were gathered at two measurement times. Increases in group participation were positively related to increases in group potency and the convergence in beliefs about group effectiveness among group members over time. Results supported the premise that group performance feedback is an antecedent of changes in group potency over time.
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Gal, S; Lichtenberg, D; Bor, A; Pinchuk, I
2007-12-01
Copper-induced peroxidation of liposomal palmitoyllinoleoyl-phosphatidylcholine (PLPC) is inhibited by alpha-tocopherol at micromolar concentrations. In our previous study we found that when the liposomes contain phosphatidylserine (PS), nanomolar concentrations of Toc were sufficient to inhibit peroxidation. In an attempt to gain understanding of the origin of this extreme antioxidative potency, we tested the antioxidative potency of 36 additional antioxidants and the dependence of their potency on the presence of PS in the liposomes. The results of these studies reveal that only 11 of the tested antioxidants possess similar antioxidative potency to that of Toc. These include trolox, butylated hydroxytoluene (BHT), curcumin, nordihydroguaiaretic acid (NDGA), diethylstilbestrol (DES), 2 of the 13 tested flavonoids (luteolin and 7,3',4'-trihydroxyflavone; T-414), alpha-naphthol, 1,5-, 1,6- and 1,7-dihydroxynaphthalenes (DHNs). Propyl gallate (PG), methyl syringate, rosmarinic acid, resveratrol, other flavonoids, as well as beta-naphthol, 1,2-, 1,3-, 1,4-, 2,3-, 2,6-, and 2,7-DHNs were either moderately antioxidative or pro-oxidative. For liposomes made of PLPC (250 microM) and PS (25 microM) the "lag" preceding copper-induced peroxidation (5 microM copper) was doubled upon addition of 30-130nM of the "super-active" antioxidants. We propose that the mechanism responsible for the extreme antioxidative potency against copper-induced peroxidation in PS-containing liposomes involves replenishment of the antioxidant in a ternary PS-copper-antioxidant complex. Based on structure-activity relationship of the 37 tested antioxidants, the "super-antioxidative potency" is attributed to the recycling of relatively stable semiquinone or semiquinone-like radicals.
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Ghosh, Probir Kumar; Bhattacharjee, Paramita; Das, Satadal
2016-01-01
Antimicrobial potency of herbal extracts is well known. The review of patents and research articles revealed that several herbal extracts have been employed in the formulation of topical products such as creams, exclusive of the cream reported in the present study. 0ur previous study has established antimicrobial potency of supercritical carbon dioxide extracts of tuberose flowers, better known for its sweet fragrance. The present work focuses on formulating a topical antimicrobial herbal cream with methyl eugenol (principal antimicrobial compound) rich - supercritical carbon dioxide extract of tuberose flowers, having good combination of phytochemical and antimicrobial potencies. Supercritical carbon dioxide parameters such as temperature, pressure and time were optimized using full factorial experimental design to obtain methyl eugenol-rich extracts. A cream was formulated using the extract having the best combination of phytochemical and antimicrobial potencies and was assayed further for in vitro antimicrobial potency; physiochemical and sensory properties. Two commercial antimicrobial cream samples were used as reference samples in the study. The extract obtained at 40°C, 10 MPa, 135 min at 1 L min-1 flow rate of gaseous C02 showed the best combination of phytochemical and antimicrobial potencies and was used for formulation of herbal creams. The cream formulated with 5% w/w of extract arrested growth of the common human skin pathogen Staphylococcus aureus and showed stable physiochemical properties and high sensory appeal for a year. The cream could be considered as a 'finished herbal product&' in compliance with the World Health 0rganization guidelines.
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Role of Homologous Fc Fragment in the Potency and Efficacy of Anti-Botulinum Antibody Preparations.
Torgeman, Amram; Ozeri, Eyal; Ben David, Alon; Diamant, Eran; Rosen, Osnat; Schwartz, Arieh; Barnea, Ada; Makovitzki, Arik; Mimran, Avishai; Zichel, Ran
2017-05-29
The only approved treatment for botulism relies on passive immunity which is mostly based on antibody preparations collected from hyper-immune horses. The IgG Fc fragment is commonly removed from these heterologous preparations to reduce the incidence of hyper-sensitivity reactions. New-generation therapies entering the pipeline are based on a combination of humanized monoclonal antibodies (MAbs), which exhibit improved safety and pharmacokinetics. In the current study, a systematic and quantitative approach was applied to measure the direct contribution of homologous Fc to the potency of monoclonal and polyclonal antitoxin preparations in mice. Homologous Fc increased the potency of three individual anti-botulinum toxin MAbs by up to one order of magnitude. Moreover, Fc fragment removal almost completely abolished the synergistic potency obtained from a combined preparation of these three MAbs. The MAb mixture neutralized a 400-mouse median lethal dose (MsLD50) of botulinum toxin, whereas the F(ab')2 combination failed to neutralize 10 MsLD50 of botulinum toxin. Notably, increased avidity did not compensate for this phenomenon, as a polyclonal, hyper-immune, homologous preparation lost 90% of its potency as well upon Fc removal. Finally, the addition of homologous Fc arms to a heterologous pharmaceutical anti-botulinum toxin polyclonal horse F(ab')2 preparation improved its efficacy when administered to intoxicated symptomatic mice. Our study extends the aspects by which switching from animal-based to human-based antitoxins will improve not only the safety but also the potency and efficacy of passive immunity against toxins.
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Small difference in carcinogenic potency between GBP nanomaterials and GBP micromaterials.
Gebel, Thomas
2012-07-01
Materials that can be described as respirable granular biodurable particles without known significant specific toxicity (GBP) show a common mode of toxicological action that is characterized by inflammation and carcinogenicity in chronic inhalation studies in the rat. This study was carried out to compare the carcinogenic potency of GBP nanomaterials (primary particle diameter 1-100 nm) to GBP micromaterials (primary particle diameter >100 nm) in a pooled approach. For this purpose, the positive GBP rat inhalation carcinogenicity studies have been evaluated. Inhalation studies on diesel engine emissions have also been included due to the fact that the mode of carcinogenic action is assumed to be the same. As it is currently not clear which dose metrics may best explain carcinogenic potency, different metrics have been considered. Cumulative exposure concentrations related to mass, surface area, and primary particle volume have been included as well as cumulative lung burden metrics related to mass, surface area, and primary particle volume. In total, 36 comparisons have been conducted. Including all dose metrics, GBP nanomaterials were 1.33- to 1.69-fold (mean values) and 1.88- to 3.54-fold (median values) more potent with respect to carcinogenicity than GBP micromaterials, respectively. Nine of these 36 comparisons showed statistical significance (p < 0.05, U test), all of which related to dose metrics based on particle mass. The maximum comparative potency factor obtained for one of these 9 dose metric comparisons based on particle mass was 4.71. The studies with diesel engine emissions did not have a major impact on the potency comparison. The average duration of the carcinogenicity studies with GBP nanomaterials was 4 months longer (median values 30 vs. 26 months) than the studies with GBP micromaterials, respectively. Tumor rates increase with age and lung tumors in the rat induced by GBP materials are known to appear late, that is, mainly after study durations longer than 24 months. Taking the different study durations into account, the real potency differences were estimated to be twofold lower than the relative potency factors identified. In conclusion, the chronic rat inhalation studies with GBP materials indicate that the difference in carcinogenic potency between GBP nanomaterials and GBP micromaterials is low can be described by a factor of 2-2.5 referring to the dose metrics mass concentration.
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Kimball, F A; Frielink, R D; Porteus, S E
1978-01-01
Male Spraque-Dawley rats receiving implants of silicone rubber discs containing 1% or 2% 15(S)-15-methyl prostaglandin F2 alpha methyl ester (15-Me-PGF 2 alpha) or no prostaglandin were tested in successive breeding trials for potency and fertility. One week after implantation, discs containing 1% 15-Me-PGF2 alpha reduced potency and fertility, which returned 2 weeks after implantation. Animals receiving implants of the 2% discs were apparently impotent the 1st week following implantation; potency returned before full fertility returned 11 weeks after implantation.
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Dinkova-Kostova, Albena T; Talalay, Paul; Sharkey, John; Zhang, Ying; Holtzclaw, W David; Wang, Xiu Jun; David, Emilie; Schiavoni, Katherine H; Finlayson, Stewart; Mierke, Dale F; Honda, Tadashi
2010-10-29
The Keap1/Nrf2/ARE pathway controls a network of cytoprotective genes that defend against the damaging effects of oxidative and electrophilic stress, and inflammation. Induction of this pathway is a highly effective strategy in combating the risk of cancer and chronic degenerative diseases, including atherosclerosis and neurodegeneration. An acetylenic tricyclic bis(cyano enone) bearing two highly electrophilic Michael acceptors is an extremely potent inducer in cells and in vivo. We demonstrate spectroscopically that both cyano enone functions of the tricyclic molecule react with cysteine residues of Keap1 and activate transcription of cytoprotective genes. Novel monocyclic cyano enones, representing fragments of rings A and C of the tricyclic compound, reveal that the contribution to inducer potency of the ring C Michael acceptor is much greater than that of ring A, and that potency is further enhanced by spatial proximity of an acetylenic function. Critically, the simultaneous presence of two cyano enone functions in rings A and C within a rigid three-ring system results in exceptionally high inducer potency. Detailed understanding of the structural elements that contribute to the reactivity with the protein sensor Keap1 and to high potency of induction is essential for the development of specific and selective lead compounds as clinically relevant chemoprotective agents.
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A new series of highly potent growth hormone-releasing peptides derived from ipamorelin.
Ankersen, M; Johansen, N L; Madsen, K; Hansen, B S; Raun, K; Nielsen, K K; Thogersen, H; Hansen, T K; Peschke, B; Lau, J; Lundt, B F; Andersen, P H
1998-09-10
A new series of GH secretagogues derived from ipamorelin is described. In an attempt to obtain oral bioavailability, by reducing the size and the number of potential hydrogen-bonding sites of the compounds, a strategy using the peptidomimetic fragment 3-(aminomethyl)benzoic acid and sequential backbone N-methylations was applied. Several compounds from this series release GH with high in vitro potency and efficacy in a rat pituitary cell assay and high in vivo potency and efficacy in anesthetized rats. The tetrapeptide NNC 26-0235 (3-(aminomethyl)benzoyl-D-2Nal-N-Me-D-Phe-Lys-NH2) shows, following iv administration, comparable in vivo potency to ipamorelin, GHRP-2, and GHRP-6 with an ED50 in swine at 2 nmol/kg. NNC 26-0235 demonstrated a 10% oral bioavailability in dogs, and NNC 26-0235 and ipamorelin were able to increase basal GH level by more than 10-fold after oral administration of a dose of 1.8 and 2.7 mg/kg, respectively. The tripeptide NNC 26-0323 (3-(aminomethyl)benzoic acid-N-Me-D-2Nal-N-Me-D-Phe-ol) which showed moderate in vitro potency but lacked in vivo potency demonstrated a 20% oral bioavailability in rats.
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Gross, S; Janssen, S W J; de Vries, B; Terao, E; Daas, A; Buchheit, K-H
2010-07-01
An international collaborative study to validate 2 alternative in vitro methods for the potency testing of human tetanus immunoglobulin products was organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM). The study, run in the framework of the Biological Standardisation Programme (BSP) under the aegis of the European Commission and the Council of Europe, involved 21 official medicines control and industry laboratories from 15 countries. Both methods, an enzyme-linked immunoassay (EIA) and a toxoid inhibition assay (TIA), showed good reproducibility, repeatability and precision. EIA and TIA discriminated between low, medium and high potency samples. Potency estimates correlated well and both values were in close agreement with those obtained by in vivo methods. Moreover, these alternative methods allowed to resolve discrepant results between laboratories that were due to product potency loss and reporting errors. The study demonstrated that EIA and TIA are suitable quality control methods for tetanus immunoglobulin, which can be standardised in a control laboratory using a quality assurance system. Consequently, the Group of Experts on Human Blood and Blood Products of the European Pharmacopoeia revised the monograph on human tetanus immunoglobulins to include both the methods as compendial alternatives to the in vivo mouse challenge assay. 2010 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.
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Shi, Wei; Wei, Si; Hu, Xin-xin; Hu, Guan-jiu; Chen, Cu-lan; Wang, Xin-ru; Giesy, John P.; Yu, Hong-xia
2013-01-01
Some synthetic chemicals, which have been shown to disrupt thyroid hormone (TH) function, have been detected in surface waters and people have the potential to be exposed through water-drinking. Here, the presence of thyroid-active chemicals and their toxic potential in drinking water sources in Yangtze River Delta were investigated by use of instrumental analysis combined with cell-based reporter gene assay. A novel approach was developed to use Monte Carlo simulation, for evaluation of the potential risks of measured concentrations of TH agonists and antagonists and to determine the major contributors to observed thyroid receptor (TR) antagonist potency. None of the extracts exhibited TR agonist potency, while 12 of 14 water samples exhibited TR antagonistic potency. The most probable observed antagonist equivalents ranged from 1.4 to 5.6 µg di-n-butyl phthalate (DNBP)/L, which posed potential risk in water sources. Based on Monte Carlo simulation related mass balance analysis, DNBP accounted for 64.4% for the entire observed antagonist toxic unit in water sources, while diisobutyl phthalate (DIBP), di-n-octyl phthalate (DNOP) and di-2-ethylhexyl phthalate (DEHP) also contributed. The most probable observed equivalent and most probable relative potency (REP) derived from Monte Carlo simulation is useful for potency comparison and responsible chemicals screening. PMID:24204563
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Opportunities and strategies to further reduce animal use for Leptospira vaccine potency testing.
Walker, A; Srinivas, G B
2013-09-01
Hamsters are routinely infected with virulent Leptospira for two purposes in the regulation of biologics: the performance of Codified potency tests and maintenance of challenge culture for the Codified potency tests. Options for reducing animal use in these processes were explored in a plenary lecture at the "International Workshop on Alternative Methods for Leptospira Vaccine Potency Testing: State of the Science and the Way Forward" held at the Center for Veterinary Biologics in September 2012. The use of validated in vitro potency assays such as those developed by the U.S. Department of Agriculture for Leptospira (L.) canicola, Leptospira grippotyphosa, Leptospira pomona, and Leptospira icterohaemorrhagiae rather than the Codified hamster vaccination-challenge assay was encouraged. Alternatives such as reduced animal numbers in the hamster vaccination-challenge testing were considered for problematic situations. Specifically, the merits of sharing challenge controls, reducing group sizes, and eliminating animals for concurrent challenge dose titration were assessed. Options for maintaining virulent, stable cultures without serial passage through hamsters or with decreased hamster use were also discussed. The maintenance of virulent Leptospira without the use of live animals is especially difficult since a reliable means to maintain virulence after multiple in vitro passages has not yet been identified. Published by Elsevier Ltd.
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Yao, Chunhe; Carlisi, Cristina; Li, Yuning; Chen, Da; Ding, Jianfu; Feng, Yong-Lai
2016-01-01
Increasing use of single-walled carbon nanotubes (SWCNTs) necessitates a novel method for hazard risk assessment. In this work, we investigated the interaction of several types of commercial SWCNTs with single-stranded (ss) and double-stranded (ds) DNA oligonucleotides (20-mer and 20 bp). Based on the results achieved, we proposed a novel assay that employed the DNA interaction potency to assess the hazard risk of SWCNTs. It was found that SWCNTs in different sizes or different batches of the same product number of SWCNTs showed dramatically different potency of interaction with DNAs. In addition, the same SWCNTs also exerted strikingly different interaction potency with ss- versus ds- DNAs. The interaction rates of SWCNTs with DNAs were investigated, which could be utilized as the indicator of potential hazard for acute exposure. Compared to solid SWCNTs, the SWCNTs dispersed in liquid medium (2% sodium cholate solution) exhibited dramatically different interaction potency with DNAs. This indicates that the exposure medium may greatly influence the subsequent toxicity and hazard risk produced by SWCNTs. Based on the findings of dose-dependences and time-dependences from the interactions between SWCNTs and DNAs, a new chemistry based assay for hazard risk assessment of nanomaterials including SWCNTs has been presented. PMID:27936089
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Yao, Chunhe; Carlisi, Cristina; Li, Yuning; Chen, Da; Ding, Jianfu; Feng, Yong-Lai
2016-01-01
Increasing use of single-walled carbon nanotubes (SWCNTs) necessitates a novel method for hazard risk assessment. In this work, we investigated the interaction of several types of commercial SWCNTs with single-stranded (ss) and double-stranded (ds) DNA oligonucleotides (20-mer and 20 bp). Based on the results achieved, we proposed a novel assay that employed the DNA interaction potency to assess the hazard risk of SWCNTs. It was found that SWCNTs in different sizes or different batches of the same product number of SWCNTs showed dramatically different potency of interaction with DNAs. In addition, the same SWCNTs also exerted strikingly different interaction potency with ss- versus ds- DNAs. The interaction rates of SWCNTs with DNAs were investigated, which could be utilized as the indicator of potential hazard for acute exposure. Compared to solid SWCNTs, the SWCNTs dispersed in liquid medium (2% sodium cholate solution) exhibited dramatically different interaction potency with DNAs. This indicates that the exposure medium may greatly influence the subsequent toxicity and hazard risk produced by SWCNTs. Based on the findings of dose-dependences and time-dependences from the interactions between SWCNTs and DNAs, a new chemistry based assay for hazard risk assessment of nanomaterials including SWCNTs has been presented.
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NASA Astrophysics Data System (ADS)
Martín-Méndez, Iván; Boixereu, Ester; Villaseca, Carlos
2016-06-01
Graphite is found dispersed in high-grade metapelitic rocks of the Anatectic Complex of Toledo (ACT) and was mined during the mid twentieth century in places where it has been concentrated (Guadamur and la Puebla de Montalbán mines). Some samples from these mines show variable but significant alteration intensity, reaching very low-T hydrothermal (supergene) conditions for some samples from the waste heap of the Guadamur site (<100 °C and 1 kbar). Micro-Raman and XRD data indicate that all the studied ACT graphite is of high crystallinity irrespective of the degree of hydrothermal alteration. Chemical differences were obtained for graphite δ13C composition. ACT granulitic graphite shows δ13CPDB values in the range of -20.5 to -27.8 ‰, indicating a biogenic origin. Interaction of graphite with hydrothermal fluids does not modify isotopic compositions even in the most transformed samples from mining sites. The different isotopic signatures of graphite from the mining sites reflect its contrasted primary carbon source. The high crystallinity of studied graphite makes this area of central Spain suitable for graphitic exploration and its potential exploitation, due to the low carbon content required for its viability and its strategic applications in advanced technologies, such as graphene synthesis.
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Inhaled asbestos fibers result in respiratory diseases such as asbestosis, lung cancer and mesothelioma, but different asbestos fibers exhibit different potency. We applied a recently developed dosimetry model (Asgharian et al., Poster # 104) that describes th...
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An Integrated View of Air Mutagenicity
The mutagenic potency of ambient air particulate material (PM) in the Salmonella mutagenicity assay (revertants/mg PM) varies only ~1 order of magnitude worldwide; however, the mutagenic potency of the air itself (revertants/m3 of air) varies ~5 orders of magnitude (IARC Monograp...
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21 CFR 660.25 - Potency tests without reference preparations.
Code of Federal Regulations, 2012 CFR
2012-04-01
... manufacturer's package insert using red blood cells showing heterozygous or diminished expression of the... SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Blood Grouping Reagent § 660.25 Potency tests without reference preparations. Products for which Reference Blood...
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21 CFR 660.25 - Potency tests without reference preparations.
Code of Federal Regulations, 2010 CFR
2010-04-01
... manufacturer's package insert using red blood cells showing heterozygous or diminished expression of the... SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Blood Grouping Reagent § 660.25 Potency tests without reference preparations. Products for which Reference Blood...
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21 CFR 660.25 - Potency tests without reference preparations.
Code of Federal Regulations, 2014 CFR
2014-04-01
... manufacturer's package insert using red blood cells showing heterozygous or diminished expression of the... SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Blood Grouping Reagent § 660.25 Potency tests without reference preparations. Products for which Reference Blood...
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21 CFR 660.25 - Potency tests without reference preparations.
Code of Federal Regulations, 2011 CFR
2011-04-01
... manufacturer's package insert using red blood cells showing heterozygous or diminished expression of the... SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Blood Grouping Reagent § 660.25 Potency tests without reference preparations. Products for which Reference Blood...
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21 CFR 660.25 - Potency tests without reference preparations.
Code of Federal Regulations, 2013 CFR
2013-04-01
... manufacturer's package insert using red blood cells showing heterozygous or diminished expression of the... SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Blood Grouping Reagent § 660.25 Potency tests without reference preparations. Products for which Reference Blood...
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Takeyoshi, Masahiro; Iida, Kenji; Shiraishi, Keiji; Hoshuyama, Satsuki
2005-01-01
The murine local lymph node assay (LLNA) is currently recognized as a stand-alone sensitization test for determining the sensitizing potential of chemicals, and it has the advantage of yielding a quantitative endpoint that can be used to predict the sensitization potency of chemicals. The EC3 has been proposed as a parameter for classifying chemicals according to the sensitization potency. We previously developed a non-radioisotopic endpoint for the LLNA based on 5-bromo-2'-deoxyuridine (BrdU) incorporation (non-RI LLNA), and we are proposing a new procedure to predict the sensitization potency of chemicals based on comparisons with known human contact allergens. Nine chemicals (i.e. diphencyclopropenone, p-phenylenediamine, glutaraldehyde, cinnamicaldehyde, citral, eugenol, isopropyl myristate, propyleneglycol and hexane) categorized as human contact allergen classes 1-5 were tested by the non-RI LLNA with the following reference allergens: 2,4-dinitrochlorobenzene (DNCB) as a class 1 human contact allergen, isoeugenol as a class 2 human contact allergen and alpha-hexylcinnamic aldehyde (HCA) as a class 3 human contact allergen. Consequently, nine test chemicals were almost assigned to their correct allergen class. The results suggested that the new procedure for non-RI LLNA can provide correct sensitization potency data. Sensitization potency data are useful for evaluating the sensitization risk to humans of exposure to new chemical products. Accordingly, this approach would be an effective modification of LLNA with regard to its experimental design. Moreover, this procedure can be applied also to the standard LLNA with radioisotopes and to other modifications of the LLNA. Copyright 2005 John Wiley & Sons, Ltd.
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Pershing, Lynn K; Reilly, Christopher A; Corlett, Judy L; Crouch, Dennis J
2006-01-01
Historically, pepper spray product potency has been established using a taste test evaluation. A taste test is subjective and may not be appropriate for assessing pepper potency in skin. The current study evaluated chemically diverse pepper sprays in human forearm skin using three objective, noninvasive parameters: transepidermal water loss, skin surface temperature and erythema, as a means for assessing dermal pharmacology, toxicology and product potency. Five commercial pepper spray products containing various capsaicinoid analogs at various concentrations were evaluated in duplicate on volar forearms of six Caucasians and six Asians using a 10 min exposure. Mean surface skin temperature, transepidermal water loss results were highly variable and therefore did not demonstrate dose responsive behavior to increasing capsaicinoid concentrations. Erythema, as measured by increases in a* (reflected light in the red-to-green color spectrum) of the L*a*b* uniform color scale, was superior among parameters evaluated in discriminating pepper spray potency and correlated well with the relative and total capsaicinoid concentration in the products. Products containing greater than 16 mg ml(-1) capsaicinoid concentration produced greater erythema responses in Caucasians than Asians. Asians responded greater to the synthetic analog, nonivamide, than to mixtures of capsaicinoids, while Caucasians responded equally to both capsaicinoid analogs. Thus, pepper spray product potency in human skin reflects the total capsaicinoid concentration, the specific capsaicin analog(s) present, and the race of the individual exposed. The finding that the reflectance colorimeter a* scale can differentiate these parameters in skin will have a significant impact on evaluating the use and efficacy of pepper spray products in humans. 2005 John Wiley & Sons, Ltd.
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Development of a surrogate angiogenic potency assay for clinical-grade stem cell production.
Lehman, Nicholas; Cutrone, Rochelle; Raber, Amy; Perry, Robert; Van't Hof, Wouter; Deans, Robert; Ting, Anthony E; Woda, Juliana
2012-09-01
Clinical results from acute myocardial infarction (AMI) patients treated with MultiStem®, a large-scale expanded adherent multipotent progenitor cell population (MAPC), have demonstrated a strong safety and benefit profile for these cells. The mechanism of benefit with MAPC treatment is a result, in part, of its ability to induce neovascularization through trophic support. Production of clinical-grade stem cell products requires the development of lot-release criteria based on potency assays that directly reflect the fundamental mechanistic pathway underlying the therapeutic response to verify manufacturing process consistency and product potency. Using an in vitro endothelial tube formation assay, a potency assay has been developed that reflects MAPC pro-angiogenic activity. Serum-free conditioned media collected from MAPC culture induced endothelial tube formation. A proteomic survey of angiogenic factors produced by the cells in vitro revealed candidate factors linked to angiogenic potency. Three cytokines, chemokine (C-X-C motif) ligand 5 (CXCL5), interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF), were required for this angiogenic activity. Depletion of any of these factors from the media prevented tube formation, while adding back increasing amounts of these cytokines into the depleted serum-free conditioned media established the lower limits of each of the cytokines required to induce angiogenesis. A necessary threshold of angiogenic factor expression was established using an in vitro angiogenesis assay. By correlating the levels of the cytokines required to induce tube formation in vitro with levels of the factors found in the spent media from manufacturing production runs, detection of these factors was identified as a surrogate potency assay with defined pass/fail criteria.
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Schmeisser, Falko; Jing, Xianghong; Joshi, Manju; Vasudevan, Anupama; Soto, Jackeline; Li, Xing; Choudhary, Anil; Baichoo, Noel; Resnick, Josephine; Ye, Zhiping; McCormick, William; Weir, Jerry P
2016-03-01
The potency of inactivated influenza vaccines is determined using a single-radial immunodiffusion (SRID) assay and requires standardized reagents consisting of a Reference Antigen and an influenza strain-specific antiserum. Timely availability of reagents is a critical step in influenza vaccine production, and the need for backup approaches for reagent preparation is an important component of pandemic preparedness. When novel H7N9 viruses emerged in China in 2013, candidate inactivated H7N9 influenza vaccines were developed for evaluation in clinical trials, and reagents were needed to measure vaccine potency. We previously described an alternative approach for generating strain-specific potency antisera, utilizing modified vaccinia virus Ankara vectors to produce influenza hemagglutinin (HA)-containing virus-like particles (VLPs) for immunization. Vector-produced HA antigen is not dependent upon the success of the traditional bromelain-digestion and HA purification. Antiserum for H7N9 vaccines, produced after immunization of sheep with preparations of bromelain-HA (br-HA), was not optimal for the SRID assay, and the supply of antiserum was limited. However, antiserum obtained from sheep boosted with VLPs containing H7 HA greatly improved the ring quality in the SRID assay. Importantly, this antiserum worked well with both egg- and cell-derived antigen and was distributed to vaccine manufacturers. Utilizing a previously developed approach for preparing vaccine potency antiserum, we have addressed a major bottleneck encountered in preparation of H7N9 vaccine reagents. The combination of br-HA and mammalian VLPs for sequential immunization represents the first use of an alternative approach for producing an influenza vaccine potency antiserum. © 2015 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.
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Statistical analysis of radioimmunoassay. In comparison with bioassay (in Japanese)
DOE Office of Scientific and Technical Information (OSTI.GOV)
Nakano, R.
1973-01-01
Using the data of RIA (radioimmunoassay), statistical procedures for dealing with two problems of the linearization of dose response curve and calculation of relative potency were described. There were three methods for linearization of dose response curve of RIA. In each method, the following parameters were shown on the horizontal and vertical axis: dose x, (B/T)/sup -1/; c/x + c, B/T (C: dose which makes B/T 50%); log x, logit B/T. Among them, the last method seems to be most practical. The statistical procedures for bioassay were employed for calculating the relative potency of unknown samples compared to the standardmore » samples from dose response curves of standand and unknown samples using regression coefficient. It is desirable that relative potency is calculated by plotting more than 5 points in the standard curve and plotting more than 2 points in unknow samples. For examining the statistical limit of precision of measuremert, LH activity of gonadotropin in urine was measured and relative potency, precision coefficient and the upper and lower limits of relative potency at 95% confidence limit were calculated. On the other hand, bioassay (by the ovarian ascorbic acid reduction method and anteriol lobe of prostate weighing method) was done in the same samples, and the precision was compared with that of RIA. In these examinations, the upper and lower limits of the relative potency at 95% confidence limit were near each other, while in bioassay, a considerable difference was observed between the upper and lower limits. The necessity of standardization and systematization of the statistical procedures for increasing the precision of RIA was pointed out. (JA)« less
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Prediction of skin sensitization potency using machine learning approaches.
Zang, Qingda; Paris, Michael; Lehmann, David M; Bell, Shannon; Kleinstreuer, Nicole; Allen, David; Matheson, Joanna; Jacobs, Abigail; Casey, Warren; Strickland, Judy
2017-07-01
The replacement of animal use in testing for regulatory classification of skin sensitizers is a priority for US federal agencies that use data from such testing. Machine learning models that classify substances as sensitizers or non-sensitizers without using animal data have been developed and evaluated. Because some regulatory agencies require that sensitizers be further classified into potency categories, we developed statistical models to predict skin sensitization potency for murine local lymph node assay (LLNA) and human outcomes. Input variables for our models included six physicochemical properties and data from three non-animal test methods: direct peptide reactivity assay; human cell line activation test; and KeratinoSens™ assay. Models were built to predict three potency categories using four machine learning approaches and were validated using external test sets and leave-one-out cross-validation. A one-tiered strategy modeled all three categories of response together while a two-tiered strategy modeled sensitizer/non-sensitizer responses and then classified the sensitizers as strong or weak sensitizers. The two-tiered model using the support vector machine with all assay and physicochemical data inputs provided the best performance, yielding accuracy of 88% for prediction of LLNA outcomes (120 substances) and 81% for prediction of human test outcomes (87 substances). The best one-tiered model predicted LLNA outcomes with 78% accuracy and human outcomes with 75% accuracy. By comparison, the LLNA predicts human potency categories with 69% accuracy (60 of 87 substances correctly categorized). These results suggest that computational models using non-animal methods may provide valuable information for assessing skin sensitization potency. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.
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Jobski, K; Kollhorst, B; Schink, T; Garbe, Edeltraut
2015-09-01
Intoxications involving prescription opioids are a major public health problem in many countries. When taken with opioids, alcohol can enhance the effects of opioids, particularly in the central nervous system. However, data quantifying the impact of alcohol involvement in opioid-related intoxications are limited. Using claims data from the German Pharmacoepidemiological Research Database (GePaRD), we conducted a retrospective cohort study based on users of high-potency opioid (HPO) analgesics during the years 2005-2009. HPO use was classified as extended-release, immediate-release or both. We calculated incidence rates (IRs) for opioid intoxications or related events as well as adjusted IR ratios (aIRR) comparing HPO-treated patients with alcohol-related disorders (ARDs) to those without ARDs overall and within each HPO category. During the study period, 308,268 HPO users were identified with an overall IR of 340.4 per 100,000 person-years [95 % confidence interval (CI) 325.5-355.7]. The risk was highest when patients received concomitant treatment with extended- and immediate-release HPOs (IR 1093.8; 95 % CI 904.6-1310.9). ARDs increased the risk during HPO use by a factor of 1.7 and the highest aIRR was seen when comparing patients simultaneously exposed to extended- and immediate-release HPOs with ARDs to those without ARD also after excluding patients with potential improper/non-medical HPO use. Physicians should be aware of these elevated risks in HPO patients with ARDs. Active patient education by healthcare providers regarding the risk of opioid intoxications or related events due to alcohol in conjunction with HPOs is warranted.
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Natural products used as a chemical library for protein-protein interaction targeted drug discovery.
Jin, Xuemei; Lee, Kyungro; Kim, Nam Hee; Kim, Hyun Sil; Yook, Jong In; Choi, Jiwon; No, Kyoung Tai
2018-01-01
Protein-protein interactions (PPIs), which are essential for cellular processes, have been recognized as attractive therapeutic targets. Therefore, the construction of a PPI-focused chemical library is an inevitable necessity for future drug discovery. Natural products have been used as traditional medicines to treat human diseases for millennia; in addition, their molecular scaffolds have been used in diverse approved drugs and drug candidates. The recent discovery of the ability of natural products to inhibit PPIs led us to use natural products as a chemical library for PPI-targeted drug discovery. In this study, we collected natural products (NPDB) from non-commercial and in-house databases to analyze their similarities to small-molecule PPI inhibitors (iPPIs) and FDA-approved drugs by using eight molecular descriptors. Then, we evaluated the distribution of NPDB and iPPIs in the chemical space, represented by the molecular fingerprint and molecular scaffolds, to identify the promising scaffolds, which could interfere with PPIs. To investigate the ability of natural products to inhibit PPI targets, molecular docking was used. Then, we predicted a set of high-potency natural products by using the iPPI-likeness score based on a docking score-weighted model. These selected natural products showed high binding affinities to the PPI target, namely XIAP, which were validated in an in vitro experiment. In addition, the natural products with novel scaffolds might provide a promising starting point for further medicinal chemistry developments. Overall, our study shows the potency of natural products in targeting PPIs, which might help in the design of a PPI-focused chemical library for future drug discovery. Copyright © 2017 Elsevier Inc. All rights reserved.
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Page, Kristin M.; Zhang, Lijun; Mendizabal, Adam; Wease, Stephen; Carter, Shelly; Shoulars, Kevin; Gentry, Tracy; Balber, Andrew E.; Kurtzberg, Joanne
2012-01-01
BACKGROUND Engraftment failure and delays, likely due to diminished cord blood unit (CBU) potency, remain major barriers to the overall success of unrelated umbilical cord blood transplantation (UCBT). To address this problem, we developed and retrospectively validated a novel scoring system, the Cord Blood Apgar (CBA), which is predictive of engraftment after UCBT. STUDY DESIGN AND METHODS In a single-center retrospective study, utilizing a database of 435 consecutive single cord myeloablative UCBTs performed between January 1, 2000, to December 31, 2008, precryopreservation and postthaw graft variables (total nucleated cell, CD34+, colony-forming units, mononuclear cell content, and volume) were initially correlated with neutrophil engraftment. Subsequently, based on the magnitude of hazard ratios (HRs) in univariate analysis, a weighted scoring system to predict CBU potency was developed using a randomly selected training data set and internally validated on the remaining data set. RESULTS The CBA assigns transplanted CBUs three scores: a precryopreservation score (PCS), a postthaw score (PTS), and a composite score (CS), which incorporates the PCS and PTS values. CBA-PCS scores, which could be used for initial unit selection, were predictive of neutrophil (CBA-PCS ≥ 7.75 vs. <7.75, HR 3.5; p < 0.0001) engraftment. Likewise, CBA-PTS and CS scores were strongly predictive of Day 42 neutrophil engraftment (CBA-PTS ≥ 9.5 vs. <9.5, HR 3.16, p < 0.0001; CBA-CS ≥ 17.75 vs. <17.75, HR 4.01, p < 0.0001). CONCLUSION The CBA is strongly predictive of engraftment after UCBT and shows promise for optimizing screening of CBU donors for transplantation. In the future, a segment could be assayed for the PTS score providing data to apply the CS for final CBU selection. PMID:21810098
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Cancer potencies of mineral and synthetic elongated particle (EP) mixtures, including fibers from asbestos, are influenced by changes in fiber dose composition, bioavailability and biodurability in combination with relevant cytotoxic dose-response relationships. A unique and com...
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Steroselective Potencies and Relative Toxicities of Coniine Enantiomers
USDA-ARS?s Scientific Manuscript database
Coniine, one of the major toxic alkaloids present in poison hemlock (Conium maculatum), occurs in two optically active forms. A comparison of the relative potencies of (+)- and (-)-coniine enantiomers has not been previously reported. In this study, we separated the enantiomers of coniine and dete...
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Stereoselective potencies and relative toxicities of y-Coniceine and N-Methylconiine enantiomers
USDA-ARS?s Scientific Manuscript database
'-Coniceine, coniine, and N-methylconiine are toxic alkaloids present in poison hemlock (Conium maculatum). We previously reported the comparison of the relative potencies of (+)- and (-)-coniine enantiomers. In this study, we synthesized '-coniceine and the enantiomers of N-methylconiine and dete...
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CUMULATIVE RISK ASSESSMENT FOR QUANTITATIVE RESPONSE DATA
The Relative Potency Factor approach (RPF) is used to normalize and combine different toxic potencies among a group of chemicals selected for cumulative risk assessment. The RPF method assumes that the slopes of the dose-response functions are all equal; but this method depends o...
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Code of Federal Regulations, 2010 CFR
2010-04-01
... the Center for Biologics Evaluation and Research, Food and Drug Administration, as indicated in... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Potency. 640.104 Section 640.104 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL...
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Code of Federal Regulations, 2011 CFR
2011-04-01
... the Center for Biologics Evaluation and Research, Food and Drug Administration, as indicated in... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Potency. 640.104 Section 640.104 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL...
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Stereoselective potencies and relative toxicities of γ-coniceine and N-methylconiine enantiomers.
Lee, Stephen T; Green, Benedict T; Welch, Kevin D; Jordan, Glenn T; Zhang, Qian; Panter, Kip E; Hughes, David; Chang, Cheng-Wei Tom; Pfister, James A; Gardner, Dale R
2013-04-15
γ-Coniceine, coniine, and N-methylconiine are toxic alkaloids present in poison hemlock (Conium maculatum). We previously reported the comparison of the relative potencies of (+)- and (-)-coniine enantiomers. In this study, we synthesized γ-coniceine and the enantiomers of N-methylconiine and determined the biological activity of γ-coniceine and each of the N-methylconiine enantiomers in vitro and in vivo. The relative potencies of these piperidine alkaloids on cells expressing human fetal muscle-type nicotinic acetylcholine receptors had the rank order of γ-coniceine > (-)-N-methylconiine > (±)-N-methylconiine > (+)-N-methylconiine. The relative lethalities of γ-coniceine and (-)-, (±)-, and (+)-N-methylconiine in vivo using a mouse bioassay were 4.4, 16.1, 17.8, and 19.2 mg/kg, respectively. The results from this study suggest γ-coniceine is a more potent agonist than the enantiomers of N-methylconiine and that there is a stereoselective difference in the in vitro potencies of the enantiomers of N-methylconiine that correlates with the relative toxicities of the enantiomers in vivo.
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The effect of electrical lighting power and irradiance on indoor-grown cannabis potency and yield.
Potter, David J; Duncombe, Paul
2012-05-01
The floral development and potencies [Δ(9) -tetrahydrocannabinol (THC) contents] of cannabis plants were compared when grown indoors under high-pressure sodium lamps consuming electrical power at three densities (270, 400, and 600 W/m(2)). After a 3-week vegetative phase, plants were grown for 8 weeks, with lamps maintaining an artificial day length of 12 h. Foliar and floral yields were measured. Gas chromatography was used to measure the content of the psychoactive cannabinoid THC. Mean yields per unit of electrical power in each lighting regime ranged from 0.9 to 1.6 g/W, the highest being achieved in the lowest irradiance regime. The individual potencies of the separated leaf and flower materials were not affected by increasing irradiance. However, there was a corresponding increase in the overall potency of the aerial plant tissue. This was because of the plants in brighter conditions producing a higher proportion of floral material. © 2011 American Academy of Forensic Sciences.
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Dioxin-like toxic potency in Forster's tern eggs from Green Bay, Lake Michigan, North America
Tillitt, D. E.; Kubiak, T.J.; Ankley, G.T.; Giesy, J.P.
1993-01-01
The endangered Forster's tern (Sternaforsteri) population on Green Bay, Wisconsin has exhibited symptoms of embryotoxicity, congenital deformities, and poor hatching success. The putative causal agents are planar halogenated hydrocarbons (PHH). The objectives of this study were: 1) to evaluate the toxic potency of PHHs in extracts of Forster's tern eggs taken from Green Bay, Lake Michigan and a reference site, Lake Poygan, WI; and 2) to compare the toxic potencies of the egg extracts with the reproductive data available from the same water bird colonies. The relative toxic potency of the egg extracts was assessed with the H4IIE bioassay system to obtain 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TCDD-EQ). The average concentrations of TCDD-EQ in Forster's tern eggs were 214.5 pg/g and 23.4 pg/g from Green Bay and Lake Poygan, respectively. The bioassay results presented here concur with the biological effects and chemical analyses information from other studies on the same Forster's tern colonies.
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Baston, David S.; Denison, Michael S.
2011-01-01
The chemically activated luciferase expression (CALUX) system is a mechanistically based recombinant luciferase reporter gene cell bioassay used in combination with chemical extraction and clean-up methods for the detection and relative quantitation of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related dioxin-like halogenated aromatic hydrocarbons in a wide variety of sample matrices. While sample extracts containing complex mixtures of chemicals can produce a variety of distinct concentration-dependent luciferase induction responses in CALUX cells, these effects are produced through a common mechanism of action (i.e. the Ah receptor (AhR)) allowing normalization of results and sample potency determination. Here we describe the diversity in CALUX response to PCDD/Fs from sediment and soil extracts and not only report the occurrence of superinduction of the CALUX bioassay, but we describe a mechanistically based approach for normalization of superinduction data that results in a more accurate estimation of the relative potency of such sample extracts. PMID:21238730
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USDA regulatory guidelines and practices for veterinary Leptospira vaccine potency testing.
Srinivas, G B; Walker, A; Rippke, B
2013-09-01
Batch-release potency testing of leptospiral vaccines licensed by the United States Department of Agriculture (USDA) historically was conducted through animal vaccination-challenge models. The hamster vaccination-challenge assay was Codified in 1974 for bacterins containing Leptospira pomona, Leptospira icterohaemorrhagiae, and Leptospira canicola, and in 1975 for bacterins containing Leptospira grippotyphosa. In brief, 10 hamsters are vaccinated with a specified dilution of bacterin. After a holding period, the vaccinated hamsters, as well as nonvaccinated controls, are challenged with virulent Leptospira and observed for mortality. Eighty percent of vaccinated hamsters must survive in the face of a valid challenge. The high cost of the Codified tests, in terms of monetary expense and animal welfare, prompted the Center for Veterinary Biologics (CVB) to develop ELISA alternatives for them. Potency tests for other serogroups, such as Leptospira hardjo-bovis, that do not have Codified requirements for potency testing continue to be examined on a case-by-case basis. Published by Elsevier Ltd.
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Slama, Rémy; Bourguignon, Jean-Pierre; Demeneix, Barbara; Ivell, Richard; Panzica, Giancarlo; Kortenkamp, Andreas; Zoeller, R Thomas
2016-10-01
Endocrine disruptors (EDs) are defined by the World Health Organization (WHO) as exogenous compounds or mixtures that alter function(s) of the endocrine system and consequently cause adverse effects in an intact organism, or its progeny, or (sub)populations. European regulations on pesticides, biocides, cosmetics, and industrial chemicals require the European Commission to establish scientific criteria to define EDs. We address the scientific relevance of four options for the identification of EDs proposed by the European Commission. Option 1, which does not define EDs and leads to using interim criteria unrelated to the WHO definition of EDs, is not relevant. Options 2 and 3 rely on the WHO definition of EDs, which is widely accepted by the scientific community, with option 3 introducing additional categories based on the strength of evidence (suspected EDs and endocrine-active substances). Option 4 adds potency to the WHO definition, as a decision criterion. We argue that potency is dependent on the adverse effect considered and is scientifically ambiguous, and note that potency is not used as a criterion to define other particularly hazardous substances such as carcinogens and reproductive toxicants. The use of potency requires a context that goes beyond hazard identification and corresponds to risk characterization, in which potency (or, more relevantly, the dose-response function) is combined with exposure levels. There is scientific agreement regarding the adequacy of the WHO definition of EDs. The potency concept is not relevant to the identification of particularly serious hazards such as EDs. As is common practice for carcinogens, mutagens, and reproductive toxicants, a multi-level classification of ED based on the WHO definition, and not considering potency, would be relevant (corresponding to option 3 proposed by the European Commission). Slama R, Bourguignon JP, Demeneix B, Ivell R, Panzica G, Kortenkamp A, Zoeller RT. 2016. Scientific issues relevant to setting regulatory criteria to identify endocrine disrupting substances in the European Union. Environ Health Perspect 124:1497-1503; http://dx.doi.org/10.1289/EHP217.
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Slama, Rémy; Bourguignon, Jean-Pierre; Demeneix, Barbara; Ivell, Richard; Panzica, Giancarlo; Kortenkamp, Andreas; Zoeller, R. Thomas
2016-01-01
Background: Endocrine disruptors (EDs) are defined by the World Health Organization (WHO) as exogenous compounds or mixtures that alter function(s) of the endocrine system and consequently cause adverse effects in an intact organism, or its progeny, or (sub)populations. European regulations on pesticides, biocides, cosmetics, and industrial chemicals require the European Commission to establish scientific criteria to define EDs. Objectives: We address the scientific relevance of four options for the identification of EDs proposed by the European Commission. Discussion: Option 1, which does not define EDs and leads to using interim criteria unrelated to the WHO definition of EDs, is not relevant. Options 2 and 3 rely on the WHO definition of EDs, which is widely accepted by the scientific community, with option 3 introducing additional categories based on the strength of evidence (suspected EDs and endocrine-active substances). Option 4 adds potency to the WHO definition, as a decision criterion. We argue that potency is dependent on the adverse effect considered and is scientifically ambiguous, and note that potency is not used as a criterion to define other particularly hazardous substances such as carcinogens and reproductive toxicants. The use of potency requires a context that goes beyond hazard identification and corresponds to risk characterization, in which potency (or, more relevantly, the dose–response function) is combined with exposure levels. Conclusions: There is scientific agreement regarding the adequacy of the WHO definition of EDs. The potency concept is not relevant to the identification of particularly serious hazards such as EDs. As is common practice for carcinogens, mutagens, and reproductive toxicants, a multi-level classification of ED based on the WHO definition, and not considering potency, would be relevant (corresponding to option 3 proposed by the European Commission). Citation: Slama R, Bourguignon JP, Demeneix B, Ivell R, Panzica G, Kortenkamp A, Zoeller RT. 2016. Scientific issues relevant to setting regulatory criteria to identify endocrine disrupting substances in the European Union. Environ Health Perspect 124:1497–1503; http://dx.doi.org/10.1289/EHP217 PMID:27108591
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Ferguson, Morag; Heath, Alan
2004-12-01
Yellow fever vaccines are routinely assayed by plaque assay. However, the results of these assays are then converted into mouse LD(50) using correlations/conversion factors which, in many cases, were established many years ago. The minimum required potency in WHO Recommendations is 10(3) LD(50)/dose. Thirteen participants from 8 countries participated in a collaborative study whose aim was to assess the suitability of two candidate preparations to serve as an International Standard for yellow fever vaccine. In addition, the study investigated the relationship between the mouse LD(50) test and plaque forming units with a view to updating the WHO recommendations. Plaque assays were more reproducible than mouse assays, as expected. Differences in sensitivities of plaque assays were observed between laboratories but these differences appear to be consistent within a laboratory for all samples and the expression of potency relative to the candidate standard vaccine improved the reproducibility of assays between laboratories. However, the use of potencies had little effect on the between laboratory variability in mouse LD(50) assays. There appears to be a consistent relationship between overall mean LD(50) and plaques titre for all study preparations other than sample E. The slope of the correlation curve is >1 and it would appear that 10(3) LD(50) is approximately equivalent to 10(4) plaque forming units (PFU), based on the overall means of all laboratory results. The First International Standard for yellow fever vaccine, NIBSC Code 99/616, has been established as the First International Standard for yellow fever vaccine by the Expert Committee of Biological Standards of the World Health Organisation. The International Standard has been arbitrarily assigned a potency of 10(4.5) International Units (IU) per ampoule. Manufacturers and National Control Laboratories are including the First International Standard for yellow fever vaccine in routine assays so that the minimum potency in IU of vaccines released for use and which meet the current minimum potency of 10(3) LD(50) in mouse assays, can be determined. These data will be analysed before a review of the WHO requirements, including the minimum potency per dose, is undertaken.
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ALTERNATIVE APPROACH TO ESTIMATING CANCER ...
The alternative approach for estimating cancer potency from inhalation exposure to asbestos seeks to improve the methods developed by USEPA (1986). This efforts seeks to modify the the current approach for estimating cancer potency for lung cancer and mesothelioma to account for the current scientific consensus that cancer risk from asbestos depends both on mineral type and on particle size distribution. In brief, epidemiological exposure-response data for lung cancer and mesothelioma in asbestos workers are combined with estimates of the mineral type(s) and partical size distribution at each exposure location in order to estimate potency factors that are specific to a selected set of mineral type and size
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Not Available
1988-06-01
4-Chloro-o-toluidine hydrochloride is a probable human carcinogen, classified as weight-of-evidence Group B2 under the EPA Guidelines for Carcinogen Risk Assessment. Evidence on potential carcinogenicity from animal studies is Sufficient, and the evidence from human studies is No Data. The potency factor (F) for 4-chloro-o-toluidine hydrochloride is estimated to be 0.40 (mg/kg/day)(-1), placing it in potency group 3 according to the CAG's methodology for evaluating potential carcinogens. Combining the weight-of-evidence group and the potency group, 4-chloro-o-toluidine hydrochloride is assigned a LOW hazard ranking.
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We have previously shown that the cytotoxic and genotoxic potency of arsenicals is dependent upon their valence and methylation state. Trivalent methylated arsenicals are much more potent DNA damaging agents than are their inorganic and pentavalent counterparts. Furthermore, thei...
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77 FR 11536 - Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM...
Federal Register 2010, 2011, 2012, 2013, 2014
2012-02-27
... Categorization of Chemicals Causing Allergic Contact Dermatitis: Availability of Federal Agency Responses AGENCY... lymph node assay (LLNA) for potency categorization of chemicals causing allergic contact dermatitis (ACD... Local Lymph Node Assay for Potency Categorization of Chemicals Causing Allergic Contact Dermatitis in...
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Cancer potencies of mineral and synthetic elongated particle (EP) mixtures, including asbestos fibers, are influenced by changes in fiber dose composition, bioavailability, and biodurability in combination with relevant cytotoxic dose-response relationships. A unique and compreh...
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Pyrethroids have emerged as a major class of insecticide due to their selective potency in insects and their relatively low potency in mammalian studies. Pyrethroids exert toxicity by binding to voltage-gated sodium channels, thereby eliciting excitatory neurotoxicity. The Food...
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Pyrethroids have emerged as a major class of insecticide due to their selective potency in insects and their relatively low potency in mammalian studies. Pyrethroids exert toxicity by binding to voltage-gated sodium channels, thereby eliciting excitatory neurotoxicity. The Fo...
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Brine Shrimp Bioassays: A Useful Technique in Biological Investigations
ERIC Educational Resources Information Center
Rice, Stanley A.; Maness, Ian B.
2004-01-01
A technique to measure the potency of leaf compounds against herbivores with the use of a bioassay is described. Bioassays are useful in classes where students have career plans like medicine in which bioassays can be used as tools for screening plants for possible medicinal potency.
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Code of Federal Regulations, 2012 CFR
2012-04-01
... STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Antibody to Hepatitis B Surface Antigen § 660.4 Potency test. To be satisfactory for release, each filling of Antibody to Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Surface Antigen Panel and shall be sufficiently potent...
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Code of Federal Regulations, 2011 CFR
2011-04-01
... STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Antibody to Hepatitis B Surface Antigen § 660.4 Potency test. To be satisfactory for release, each filling of Antibody to Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Surface Antigen Panel and shall be sufficiently potent...
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Code of Federal Regulations, 2014 CFR
2014-04-01
... STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Hepatitis B Surface Antigen § 660.43 Potency test. To be satisfactory for release, each filling of Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Antiserum Panel and shall be sufficiently potent to be able to detect the...
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Code of Federal Regulations, 2011 CFR
2011-04-01
... STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Hepatitis B Surface Antigen § 660.43 Potency test. To be satisfactory for release, each filling of Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Antiserum Panel and shall be sufficiently potent to be able to detect the...
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Code of Federal Regulations, 2014 CFR
2014-04-01
... STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Antibody to Hepatitis B Surface Antigen § 660.4 Potency test. To be satisfactory for release, each filling of Antibody to Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Surface Antigen Panel and shall be sufficiently potent...
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Code of Federal Regulations, 2012 CFR
2012-04-01
... STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Hepatitis B Surface Antigen § 660.43 Potency test. To be satisfactory for release, each filling of Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Antiserum Panel and shall be sufficiently potent to be able to detect the...
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9 CFR 113.8 - In vitro tests for serial release.
Code of Federal Regulations, 2010 CFR
2010-01-01
....8 Section 113.8 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT... Health Inspection Service (APHIS); (3) Establishing satisfactory potency for the product in accordance... potency test by Animal and Plant Health Inspection Service as provided in this paragraph. Products shall...
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Code of Federal Regulations, 2010 CFR
2010-04-01
... STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Antibody to Hepatitis B Surface Antigen § 660.4 Potency test. To be satisfactory for release, each filling of Antibody to Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Surface Antigen Panel and shall be sufficiently potent...
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Code of Federal Regulations, 2010 CFR
2010-04-01
... STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Hepatitis B Surface Antigen § 660.43 Potency test. To be satisfactory for release, each filling of Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Antiserum Panel and shall be sufficiently potent to be able to detect the...
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Simon, Eszter; van Velzen, Martin; Brandsma, Sicco H; Lie, Elisabeth; Løken, Katharina; de Boer, Jacob; Bytingsvik, Jenny; Jenssen, Bjørn M; Aars, Jon; Hamers, Timo; Lamoree, Marja H
2013-08-06
Compounds with transthyretin (TTR)-binding potency in the blood plasma of polar bear cubs were identified with effect-directed analysis (EDA). This approach contributes to the understanding of the thyroid disrupting exposome of polar bears. The selection of these samples for in-depth EDA was based on the difference between the observed TTR-binding potency on the one hand and the calculated potency (based on known concentrations of TTR-binding compounds and their relative potencies) on the other. A library-based identification was applied to the liquid chromatography-time-of-flight-mass spectrometry (LC-ToF-MS) data by screening for matches between compound lists and the LC-ToF-MS data regarding accurate mass and isotope pattern. Then, isotope cluster analysis (ICA) was applied to the LC-ToF-MS data allowing specific screening for halogen isotope patterns. The presence of linear and branched nonylphenol (NP) was observed for the first time in polar bears. Furthermore, the presence of one di- and two monohydroxylated octachlorinated biphenyls (octaCBs) was revealed in the extracts. Linear and branched NP, 4'-OH-CB201 and 4,4'-OH-CB202 could be successfully confirmed with respect to their retention time in the analytical system. In addition, branched NP, mono- and dihydroxylated-octaCBs showed TTR-binding potencies and could explain another 32 ± 2% of the total measured activities in the extracts.
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Yuen, Garmen; Khan, Fehad J.; Gao, Shaojian; Stommel, Jayne M.; Batchelor, Eric; Wu, Xiaolin
2017-01-01
Abstract CRISPR/Cas9 is a powerful gene editing tool for gene knockout studies and functional genomic screens. Successful implementation of CRISPR often requires Cas9 to elicit efficient target knockout in a population of cells. In this study, we investigated the role of several key factors, including variation in target copy number, inherent potency of sgRNA guides, and expression level of Cas9 and sgRNA, in determining CRISPR knockout efficiency. Using isogenic, clonal cell lines with variable copy numbers of an EGFP transgene, we discovered that CRISPR knockout is relatively insensitive to target copy number, but is highly dependent on the potency of the sgRNA guide sequence. Kinetic analysis revealed that most target mutation occurs between 5 and 10 days following Cas9/sgRNA transduction, while sgRNAs with different potencies differ by their knockout time course and by their terminal-phase knockout efficiency. We showed that prolonged, low level expression of Cas9 and sgRNA often fails to elicit target mutation, particularly if the potency of the sgRNA is also low. Our findings provide new insights into the behavior of CRISPR/Cas9 in mammalian cells that could be used for future improvement of this platform. PMID:29036671
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Yuen, Garmen; Khan, Fehad J; Gao, Shaojian; Stommel, Jayne M; Batchelor, Eric; Wu, Xiaolin; Luo, Ji
2017-11-16
CRISPR/Cas9 is a powerful gene editing tool for gene knockout studies and functional genomic screens. Successful implementation of CRISPR often requires Cas9 to elicit efficient target knockout in a population of cells. In this study, we investigated the role of several key factors, including variation in target copy number, inherent potency of sgRNA guides, and expression level of Cas9 and sgRNA, in determining CRISPR knockout efficiency. Using isogenic, clonal cell lines with variable copy numbers of an EGFP transgene, we discovered that CRISPR knockout is relatively insensitive to target copy number, but is highly dependent on the potency of the sgRNA guide sequence. Kinetic analysis revealed that most target mutation occurs between 5 and 10 days following Cas9/sgRNA transduction, while sgRNAs with different potencies differ by their knockout time course and by their terminal-phase knockout efficiency. We showed that prolonged, low level expression of Cas9 and sgRNA often fails to elicit target mutation, particularly if the potency of the sgRNA is also low. Our findings provide new insights into the behavior of CRISPR/Cas9 in mammalian cells that could be used for future improvement of this platform. Published by Oxford University Press on behalf of Nucleic Acids Research 2017.
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Calipari, Erin S.; Ferris, Mark J.; Siciliano, Cody A.; Zimmer, Benjamin A.
2014-01-01
Previous literature investigating neurobiological adaptations following cocaine self-administration has shown that high, continuous levels of cocaine intake (long access; LgA) results in reduced potency of cocaine at the dopamine transporter (DAT), whereas an intermittent pattern of cocaine administration (intermittent access; IntA) results in sensitization of cocaine potency at the DAT. Here, we aimed to determine whether these changes are specific to cocaine or translate to other psychostimulants. Psychostimulant potency was assessed by fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens following IntA, short access, and LgA cocaine self-administration, as well as in brain slices from naive animals. We assessed the potency of amphetamine (a releaser), and methylphenidate (a DAT blocker, MPH). MPH was selected because it is functionally similar to cocaine and structurally related to amphetamine. We found that MPH and amphetamine potencies were increased following IntA, whereas neither was changed following LgA or short access cocaine self-administration. Therefore, whereas LgA-induced tolerance at the DAT is specific to cocaine as shown in previous work, the sensitizing effects of IntA apply to cocaine, MPH, and amphetamine. This demonstrates that the pattern with which cocaine is administered is important in determining the neurochemical consequences of not only cocaine effects but potential cross-sensitization/cross-tolerance effects of other psychostimulants as well. PMID:24566123
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Villeneuve, D.L.; Crunkilton, R.L.; DeVita, W.M.
1997-05-01
Lincoln Creek is a severely degraded urban stream located in Milwaukee County, Wisconsin, USA. As part of a comprehensive study on effects of urban storm water runoff on the stream biota, an in vitro bioassay with PLHC-1 (Poeciliopsis lucida) fish hepatoma cells was used to assess potential toxic potency of aryl hydrocarbon receptor (AhR)-active compounds, collected by semipermeable membrane devices (SPMDs) exposed to Lincoln Creek water. Dialysates from SPMDs exposed to Lincoln Creek water caused marked cytochrome P4501A induction in PLHC-1. Toxic potency of dialysates, expressed as bioassay-derived 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TCDD-EQ) ranged from 1,300 to 6,600 pg TCDD-EQ/g SPMD formore » 14-d exposures. Dialysates from SPMDs exposed to stream water at base flow had potencies consistently lower than those exposed to storm-flow (high-flow) events that occurred during the same 14-d period. Polychlorinated biphenyls were not detectable in the dialysates. Gas chromatography-mass spectrometry analysis identified polycyclic aromatic hydrocarbons (PAHs) as major contaminants in the dialysates. A log-log correlation of total PAHs and TCDD-EQ yielded an r{sup 2} of 0.802. Empirical evidence suggests that AhR-active PAHs can account for about 20 to 50% of the potency observed.« less
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The Joint Task Force Structure as a Model for Homeland Security
2013-05-20
was the primary entry point for high potency marijuana and 3,4-MethyleneDioxy-n- MethylAmphetamine, ( MDMA ) known as Ecstasy bound for New York and New...into mainland Canada. Smuggling activity increased further with the rise in popularity of high potency hydroponically grown marijuana and MDMA
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High Potency and Other Alcoholic Beverage Consumption among Adolescents
ERIC Educational Resources Information Center
Jobli, Edessa C.; Dore, Heather S.; Werch, Chudley E.; Moore, Michele J.
2005-01-01
This study examined the prevalence of high potency (liquor, malt liquor, fortified wine) and other alcoholic beverage consumption (beer, wine/wine coolers) among adolescents, the impact of gender and ethnicity, and the risk and protective factors that predicted consumption. A confidential survey revealed that, among eighth grade students,…
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Developing of Environmental Education Textbook Based on Local Potencies
ERIC Educational Resources Information Center
Ilma, Silfia; Wijarini, Fitri
2017-01-01
Environmental education subject aims to form students who have the character to maintain the environment. One effort to achieve the objectives of the Environmental education subject is the local Environmental Education Textbook Based on Local Potencies. This research was aimed to produce textbook of environment-based education subject…
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Both Lymantria dispar nucleopolyhedrovirus enhancin genes contribute to viral potency
Holly J.R. Popham; David S. Bischoff; James M. Slavicek
2001-01-01
Enhancins are a group of proteins first identified in granuloviruses (GV) that have the ability to enhance nuclear polyhedrosis virus potency. We had previously identified an enhancin gene (E1) in the Lymantria dispar multinucleocapsid nucleopolyhedrovirus (LdMNPV) (D.S. Bischoff and J.M. Slavicek, J. Virol. 71:...
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Recent NHEERL research under EPA's Libby Action Plan has determined that elongated particle relative potency for rat pleural mesothelioma is best predicted on the basis of total external surface area (TSA) of slightly acid leached test samples which simulate particle bio-durabili...
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Determining the carcinogenicity and carcinogenic potency of new chemicals is both a labor-intensive and time-consuming process. In order to expedite the screening process, there is a need to either: (1) identify alternative toxicity measures (shorter duration) that may be used as...
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A CONCEPTUAL MODEL FOR EVALUATING RELATIVE POTENCY DATA FOR USE IN ECOLOGICAL RISK ASSESSMENTS
For chemicals with a common mechanism of toxicity, relative potency factors (RPFs) allow dose and exposure measures to be normalized to an equivalent toxicity amount of a model chemical... In ecological risk assessments the large number of possible target species, variety of expo...
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The botulinum toxin LD50 potency assay - another chapter, another mystery.
Pickett, Andy
2012-09-01
Observers of the potency assay used for botulinum toxin were greeted last year with the news that one company had an alternative, non-animal alternative in place. But all was not as it seemed from the press release, and over a year later, information is still lacking.
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Nikitin, N S
1977-01-01
The morphogenetic potencies of somatic cells of the fresh-water sponge Ephydatia fluviatilis in the developing aggregates depend on their initial specialization and the number of cells in the aggregate. The aggregates of nucleolar amoebocytes consisting of 500 or more cells have the highest morphogenetic potencies. All main cell types can arise in the developing homogeneous aggregates of nucleolar amoebocytes. The fine structure of nucleolar amoebocytes at different stages of development of the homogeneous aggregates was studied by means of electron microscopy. The structural rearrangements are described which accompany the process of redifferentiation of the nucleolar amoebocytes in other cell types.
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Beta-Endorphin: dissociation of receptor binding activity from analgesic potency.
Li, C H; Tseng, L F; Ferrara, P; Yamashiro, D
1980-04-01
Biological activities of synthetic camel beta-endorphin and human beta-endorphin (beta h-EP) have been measured by the radioreceptor binding assay, using [Tyr27-3H]-beta h-EP as the primary ligand and by the tail-flick test for analgesic potency. Four synthetic analogs of beta h-EP, namely [Gly31]-beta h-EP-Gly-NH2, [Gly31]-beta h-EP-Gly-Gly-NH2, [Gln8,Gly31]-beta h-EP-Gly-Gly-NH2, and [CH3(CH2)4NH231]-beta h-EP, have also been assayed by the same procedures. Results indicate a clear dissociation of radioreceptor binding activity from analgesic potency.
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Beta-Endorphin: dissociation of receptor binding activity from analgesic potency.
Li, C H; Tseng, L F; Ferrara, P; Yamashiro, D
1980-01-01
Biological activities of synthetic camel beta-endorphin and human beta-endorphin (beta h-EP) have been measured by the radioreceptor binding assay, using [Tyr27-3H]-beta h-EP as the primary ligand and by the tail-flick test for analgesic potency. Four synthetic analogs of beta h-EP, namely [Gly31]-beta h-EP-Gly-NH2, [Gly31]-beta h-EP-Gly-Gly-NH2, [Gln8,Gly31]-beta h-EP-Gly-Gly-NH2, and [CH3(CH2)4NH231]-beta h-EP, have also been assayed by the same procedures. Results indicate a clear dissociation of radioreceptor binding activity from analgesic potency. PMID:6246537
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Schaubroeck, John; Lam, Simon S K; Cha, Sandra E
2007-07-01
The authors investigated the relationship between transformational leadership behavior and group performance in 218 financial services teams that were branches of a bank in Hong Kong and the United States. Transformational leadership influenced team performance through the mediating effect of team potency. The effect of transformational leadership on team potency was moderated by team power distance and team collectivism, such that higher power distance teams and more collectivistic teams exhibited stronger positive effects of transformational leadership on team potency. The model was supported by data in both Hong Kong and the United States, which suggests a convergence in how teams function in the East and West and highlights the importance of team values.
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Synthesis and decreasing Aβ content evaluation of arctigenin-4-yl carbamate derivatives.
Xu, Xingyu; Li, Cong; Lei, Min; Zhu, Zhiyuan; Yan, Jianming; Shen, Xu; Hu, Lihong
2016-07-01
A series of arctigenin-4-yl carbamate derivatives were synthesized and evaluated for potency in reducing β-amyloid (Aβ) content in HEK293-APPswe cells. Most of the arctigenin-4-yl aralkyl or aryl carbamate derivatives showed improved potency in reducing Aβ content. Among the synthesized compounds, arctigenin-4-yl (3-chlorophenyl)carbamate (20) exhibited the strongest potency with 78.7% Aβ content reduction at 20μM. Furthermore, the effect of arctigenin-4-yl (4-chlorophenyl)carbamate (19) and arctigenin-4-yl (3-chlorophenyl)carbamate (20) on lowing Aβ content was better than arctigenin under the concentrations of 1, 10 and 20μM. Copyright © 2016 Elsevier Ltd. All rights reserved.
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A meta-analysis of asbestos-related cancer risk that addresses fiber size and mineral type.
Berman, D Wayne; Crump, Kenny S
2008-01-01
Quantitative estimates of the risk of lung cancer or mesothelioma in humans from asbestos exposure made by the U.S. Environmental Protection Agency (EPA) make use of estimates of potency factors based on phase-contrast microscopy (PCM) and obtained from cohorts exposed to asbestos in different occupational environments. These potency factors exhibit substantial variability. The most likely reasons for this variability appear to be differences among environments in fiber size and mineralogy not accounted for by PCM. In this article, the U.S. Environmental Protection Agency (EPA) models for asbestos-related lung cancer and mesothelioma are expanded to allow the potency of fibers to depend upon their mineralogical types and sizes. This is accomplished by positing exposure metrics composed of nonoverlapping fiber categories and assigning each category its own unique potency. These category-specific potencies are estimated in a meta-analysis that fits the expanded models to potencies for lung cancer (KL's) or mesothelioma (KM's) based on PCM that were calculated for multiple epidemiological studies in our previous paper (Berman and Crump, 2008). Epidemiological study-specific estimates of exposures to fibers in the different fiber size categories of an exposure metric are estimated using distributions for fiber size based on transmission electron microscopy (TEM) obtained from the literature and matched to the individual epidemiological studies. The fraction of total asbestos exposure in a given environment respectively represented by chrysotile and amphibole asbestos is also estimated from information in the literature for that environment. Adequate information was found to allow KL's from 15 epidemiological studies and KM's from 11 studies to be included in the meta-analysis. Since the range of exposure metrics that could be considered was severely restricted by limitations in the published TEM fiber size distributions, it was decided to focus attention on four exposure metrics distinguished by fiber width: "all widths," widths > 0.2 micro m, widths < 0.4 microm, and widths < 0.2 microm, each of which has historical relevance. Each such metric defined by width was composed of four categories of fibers: chrysotile or amphibole asbestos with lengths between 5 microm and 10 microm or longer than 10 microm. Using these metrics three parameters were estimated for lung cancer and, separately, for mesothelioma: KLA, the potency of longer (length > 10 microm) amphibole fibers; rpc, the potency of pure chrysotile (uncontaminated by amphibole) relative to amphibole asbestos; and rps, the potency of shorter fibers (5 microm < length < 10 microm) relative to longer fibers. For mesothelioma, the hypothesis that chrysotile and amphibole asbestos are equally potent (rpc = 1) was strongly rejected by every metric and the hypothesis that (pure) chrysotile is nonpotent for mesothelioma was not rejected by any metric. Best estimates for the relative potency of chrysotile ranged from zero to about 1/200th that of amphibole asbestos (depending on metric). For lung cancer, the hypothesis that chrysotile and amphibole asbestos are equally potent (rpc = 1) was rejected (p < or = .05) by the two metrics based on thin fibers (length < 0.4 microm and < 0.2 microm) but not by the metrics based on thicker fibers. The "all widths" and widths < 0.4 microm metrics provide the best fits to both the lung cancer and mesothelioma data over the other metrics evaluated, although the improvements are only marginal for lung cancer. That these two metrics provide equivalent (for mesothelioma) and nearly equivalent (for lung cancer) fits to the data suggests that the available data sets may not be sufficiently rich (in variation of exposure characteristics) to fully evaluate the effects of fiber width on potency. Compared to the metric with widths > 0.2 microm with both rps and rpc fixed at 1 (which is nominally equivalent to the traditional PCM metric), the "all widths" and widths < 0.4 microm metrics provide substantially better fits for both lung cancer and, especially, mesothelioma. Although the best estimates of the potency of shorter fibers (5 < length < 10 microm) is zero for the "all widths" and widths < 0.4 microm metrics (or a small fraction of that of longer fibers for the widths > 0.2 microm metric for mesothelioma), the hypothesis that these shorter fibers were nonpotent could not be rejected for any of these metrics. Expansion of these metrics to include a category for fibers with lengths < 5 microm did not find any consistent evidence for any potency of these shortest fibers for either lung cancer or mesothelioma. Despite the substantial improvements in fit over that provided by the traditional use of PCM, neither the "all widths" nor the widths < 0.4 microm metrics (or any of the other metrics evaluated) completely resolve the differences in potency factors estimated in different occupational studies. Unresolved in particular is the discrepancy in potency factors for lung cancer from Quebec chrysotile miners and workers at the Charleston, SC, textile mill, which mainly processed chrysotile from Quebec. A leading hypothesis for this discrepancy is limitations in the fiber size distributions available for this analysis. Dement et al. (2007) recently analyzed by TEM archived air samples from the South Carolina plant to determine a detailed distribution of fiber lengths up to lengths of 40 microm and greater. If similar data become available for Quebec, perhaps these two size distributions can be used to eliminate the discrepancy between these two studies.
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RELATIVE POTENCY OF MOLD AND HOUSE DUST MITE EXTRACTS IN INDUCING ALLERGIC RESPONSES IN BALB/C MICE
Rationale: Mold has been associated with the exacerbation of allergic asthma. However, its role in induction of allergic asthma is not clear. Using a previously developed mouse model for allergic asthma, we compared potencies of two fungal extracts (Metarhizium anisop...
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USDA-ARS?s Scientific Manuscript database
We evaluated the potency of 10% v/v cell-free culture supernatants of cultures of the bacteria X. bovienii, X. nematophila, X. cabanillasii, X. szentirmaii, P. temperata, P. luminescens (VS) and P. luminescens (K22) against Fusicladium carpophilum (peach scab), Fusicladium effusum (pecan scab), Moni...
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A major diesel emissions research program has been initiated by the US Environmental Protection Agency to assess the human health risk associated with increased use of diesel automobiles. This program is intended to establish the mutagenic and carcinogenic potency of complex orga...
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Benzothiophene inhibitors of MK2. Part 2: Improvements in kinase selectivity and cell potency
DOE Office of Scientific and Technical Information (OSTI.GOV)
Anderson, David R.; Meyers, Marvin J.; Kurumbail, Ravi G.
2010-10-01
Optimization of kinase selectivity for a set of benzothiophene MK2 inhibitors provided analogs with potencies of less than 500 nM in a cell based assay. The selectivity of the inhibitors can be rationalized by examination of X-ray crystal structures of inhibitors bound to MK2.
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On February 26, 2010, the draft Development of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) Mixtures document and the charge to external peer reviewers were released for external peer review and public comment. The draft document and t...
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Organophosphate (OP) and carbamate esters can inhibit acetylcholinesterase (AChE) by binding covalently to a serine residue in the enzyme active site, and their inhibitory potency depends largely on affinity for the enzyme and the reactivity of the ester. Despite this understandi...
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Relative potencies of selected dihaloacetic acids and their major metabolites in rodent whole embryo culture.
S. Hunter, M. Blanton, E. Rogers
RTD, NHEERL, ORD, US EPA, RTP, NC, 27711
Haloacetic acids (HAA) are produced by disinfection and present in tap water. S... -
9 CFR 113.116 - Pasteurella Multocida Bacterin, Avian Isolate, Type 4.
Code of Federal Regulations, 2014 CFR
2014-01-01
... turkeys during the prechallenge period of the potency test provided in paragraph (c) of this section shall... turkey, test results shall be determined by observing the remaining 20 turkeys. The test is inconclusive... more turkeys, but the serial is unsatisfactory if the test is not repeated. (c) Potency test. Bulk or...
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9 CFR 113.116 - Pasteurella Multocida Bacterin, Avian Isolate, Type 4.
Code of Federal Regulations, 2012 CFR
2012-01-01
... turkeys during the prechallenge period of the potency test provided in paragraph (c) of this section shall... turkey, test results shall be determined by observing the remaining 20 turkeys. The test is inconclusive... more turkeys, but the serial is unsatisfactory if the test is not repeated. (c) Potency test. Bulk or...
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9 CFR 113.116 - Pasteurella Multocida Bacterin, Avian Isolate, Type 4.
Code of Federal Regulations, 2011 CFR
2011-01-01
... turkeys during the prechallenge period of the potency test provided in paragraph (c) of this section shall... turkey, test results shall be determined by observing the remaining 20 turkeys. The test is inconclusive... more turkeys, but the serial is unsatisfactory if the test is not repeated. (c) Potency test. Bulk or...
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9 CFR 113.116 - Pasteurella Multocida Bacterin, Avian Isolate, Type 4.
Code of Federal Regulations, 2013 CFR
2013-01-01
... turkeys during the prechallenge period of the potency test provided in paragraph (c) of this section shall... turkey, test results shall be determined by observing the remaining 20 turkeys. The test is inconclusive... more turkeys, but the serial is unsatisfactory if the test is not repeated. (c) Potency test. Bulk or...
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9 CFR 113.116 - Pasteurella Multocida Bacterin, Avian Isolate, Type 4.
Code of Federal Regulations, 2010 CFR
2010-01-01
... turkeys during the prechallenge period of the potency test provided in paragraph (c) of this section shall... turkey, test results shall be determined by observing the remaining 20 turkeys. The test is inconclusive... more turkeys, but the serial is unsatisfactory if the test is not repeated. (c) Potency test. Bulk or...
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Arenas-Mena, Cesar; Coffman, James A.
2016-01-01
Summary It is proposed that the evolution of complex animals required repressive genetic mechanisms for controlling the transcriptional and proliferative potency of cells. Unicellular organisms are transcriptionally potent, able to express their full genetic complement as the need arises through their life cycle, whereas differentiated cells of multicellular organisms can only express a fraction of their genomic potential. Likewise, whereas cell proliferation in unicellular organisms is primarily limited by nutrient availability, cell proliferation in multicellular organisms is developmentally regulated. Repressive genetic controls limiting the potency of cells at the end of ontogeny would have stabilized the gene expression states of differentiated cells and prevented disruptive proliferation, allowing the emergence of diverse cell types and functional shapes. We propose that distal cis-regulatory elements represent the primary innovations that set the stage for the evolution of developmental gene regulatory networks and the repressive control of key multipotency and cell-cycle control genes. The testable prediction of this model is that the genomes of extant animals, unlike those of our unicellular relatives, encode gene regulatory circuits dedicated to the developmental control of transcriptional and proliferative potency. PMID:26173445
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Structure-activity relationship of tryptamine analogues on the heart of venus mercenaria
Greenberg, M. J.
1960-01-01
A number of tryptamine analogues and other exciter agents have been tested on the heart of Venus mercenaria. The method of estimation of potency, especially for irreversibly acting compounds, is discussed. Specificity of action with respect to the site of action of 5-hydroxytryptamine is defined experimentally. The specific activity of tyramine and phenethylamine and the non-specific excitatory action of indole and skatole indicate that the indole ring is neither necessary nor sufficient for 5-hydroxytryptamine-like activity. Tryptamine analogues differ in mode of action as well as potency. Congeners without a 5-hydroxyl group tend to act more slowly and irreversibly as well as less strongly than 5-hydroxytryptamine. Methyl substitution also increases the time of action and difficulty of reversal. However, the potency of such compounds may be increased or decreased depending upon the position of substitution and the presence of the 5-hydroxyl group. The relations between structure and potency and mode of action are discussed. Suggestions are made concerning the effective conformation of the 5-hydroxytryptamine molecule and the nature of its receptor. ImagesFIG. 7 PMID:13708259
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Stability of purified tuberculin in high dilution
Magnus, Knut; Guld, Johannes; Waaler, Hans; Magnusson, Mogens
1958-01-01
The authors have investigated the effect of storage on the potency of 5 TU dilutions (5 TU per 0.1 ml) of the purified tuberculin RT 19-21 (Statens Seruminstitut, Copenhagen). Dilutions stored at 2-4°C, 20°C and 37°C for different periods up to 18 months were compared by intradermal testing. About 900 BCG-vaccinated schoolchildren were given duplicate tests and in addition 500 tests were made in BCG-vaccinated guinea-pigs. The results showed unexpected variability. It appeared that this variability was due to unsystematic variations in potency both between dilutions prepared at different times and between ampoules of the same dilution. Because of this variability only limited conclusions could be drawn. At 2-4°C the effect of storage seemed to be very slight, the potency of the dilutions being reduced by less than 25% after 18 months. At the higher temperatures, the decrease in activity was more rapid. Nevertheless, the dilutions could be stored at room temperature (20°C) for some months without any practically significant loss of potency. PMID:13618718
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Schaubroeck, John M; Peng, Ann C; Hannah, Sean T
2016-02-01
We develop a model in which abusive supervision undermines individuals' perceptions of the level of respect they are accorded by their group peers, which in turn reduces their performance and disconnects them psychologically from the organization. High group potency strengthens each of these connections. We studied the theorized relationships across 3 periods during a 10-week residential organizational entry program. Group potency, representing shared group perceptions, moderated relationships at the individual level. These included the negative relationship between abusive supervision (Time 1) and perceived peer respect (Time 2) and the relationship between perceived peer respect and organizational commitment, organizational identification, and turnover intention (Time 3). We found stronger relationships between abusive supervision and perceived peer respect--and between peer respect and the attitudinal outcomes and turnover intention--among groups with higher potency. Perceived peer respect was also positively related to followers' task performance. We discuss implications of the conceptual framework and findings for future research and theory development concerning how groups and individuals respond to abusive supervision and to treatment by their peers. (c) 2016 APA, all rights reserved).
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Lee, Naery; Seo, Ji Suk; Kim, Jae Ok; Ban, Sang Ja
2017-05-01
Since the 1st Korean national biological reference standard for factor (F)VIII concentrate, established in 2001, has shown declining potency, we conducted this study to replace this standard with a 2nd Korean national biological reference standard for blood coagulation FVIII concentrate. The candidate materials for the 2nd standard were prepared in 8000 vials with 10 IU/ml of target potency, according to the approved manufacturing process of blood coagulation Factor VIII:C Monoclonal Antibody-purified, Freeze-dried Human Blood Coagulation Factor VIII:C. Potency was evaluated by one-stage clotting and chromogenic methods and the stability was confirmed to meet the specifications during a period of 73 months. Since the potencies obtained by the two methods differed significantly (P < 0.015), the values were determined separately according to the geometric means (8.9 and 7.4 IU/vial, respectively). The geometric coefficients of interlaboratory variability were 3.4% and 7.6% by the one-stage clotting and chromogenic assays, respectively. Copyright © 2017 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.
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Basic principles of stability.
Egan, William; Schofield, Timothy
2009-11-01
An understanding of the principles of degradation, as well as the statistical tools for measuring product stability, is essential to management of product quality. Key to this is management of vaccine potency. Vaccine shelf life is best managed through determination of a minimum potency release requirement, which helps assure adequate potency throughout expiry. Use of statistical tools such a least squares regression analysis should be employed to model potency decay. The use of such tools provides incentive to properly design vaccine stability studies, while holding stability measurements to specification presents a disincentive for collecting valuable data. The laws of kinetics such as Arrhenius behavior help practitioners design effective accelerated stability programs, which can be utilized to manage stability after a process change. Design of stability studies should be carefully considered, with an eye to minimizing the variability of the stability parameter. In the case of measuring the degradation rate, testing at the beginning and the end of the study improves the precision of this estimate. Additional design considerations such as bracketing and matrixing improve the efficiency of stability evaluation of vaccines.
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Gorka, Alexander P; Jacobs, Lauren M; Roepe, Paul D
2013-09-18
Drug combination therapy is the frontline of malaria treatment. There is an ever-accelerating need for new, efficacious combination therapies active against drug resistant malaria. Proven drugs already in the treatment pipeline, such as the quinolines, are important components of current combination therapy and also present an attractive test bank for rapid development of new concepts. The efficacy of several drug combinations versus chloroquine-sensitive and chloroquine-resistant strains was measured using both cytostatic and cytocidal potency assays. These screens identify quinoline and non-quinoline pairs that exhibit synergy, additivity, or antagonism using the fixed-ratio isobologram method and find tafenoquine - methylene blue combination to be the most synergistic. Also, interestingly, for selected pairs, additivity, synergy, or antagonism defined by quantifying IC50 (cytostatic potency) does not necessarily predict similar behaviour when potency is defined by LD50 (cytocidal potency). These data further support an evolving new model for quinoline anti-malarials, wherein haem and haemozoin are the principle target for cytostatic activity, but may not be the only target relevant for cytocidal activity.
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Wan, Jingjing; Huang, Johnny X; Vetter, Irina; Mobli, Mehdi; Lawson, Joshua; Tae, Han-Shen; Abraham, Nikita; Paul, Blessy; Cooper, Matthew A; Adams, David J; Lewis, Richard J; Alewood, Paul F
2015-03-11
Covalently attached peptide dendrimers can enhance binding affinity and functional activity. Homogenous di- and tetravalent dendrimers incorporating the α7-nicotinic receptor blocker α-conotoxin ImI (α-ImI) with polyethylene glycol spacers were designed and synthesized via a copper-catalyzed azide-alkyne cycloaddition of azide-modified α-ImI to an alkyne-modified polylysine dendron. NMR and CD structural analysis confirmed that each α-ImI moiety in the dendrimers had the same 3D structure as native α-ImI. The binding of the α-ImI dendrimers to binding protein Ac-AChBP was measured by surface plasmon resonance and revealed enhanced affinity. Quantitative electrophysiology showed that α-ImI dendrimers had ∼100-fold enhanced potency at hα7 nAChRs (IC50 = 4 nM) compared to native α-ImI (IC50 = 440 nM). In contrast, no significant potency enhancement was observed at heteromeric hα3β2 and hα9α10 nAChRs. These findings indicate that multimeric ligands can significantly enhance conotoxin potency and selectivity at homomeric nicotinic ion channels.
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Baston, David S; Denison, Michael S
2011-02-15
The chemically activated luciferase expression (CALUX) system is a mechanistically based recombinant luciferase reporter gene cell bioassay used in combination with chemical extraction and clean-up methods for the detection and relative quantitation of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related dioxin-like halogenated aromatic hydrocarbons in a wide variety of sample matrices. While sample extracts containing complex mixtures of chemicals can produce a variety of distinct concentration-dependent luciferase induction responses in CALUX cells, these effects are produced through a common mechanism of action (i.e. the Ah receptor (AhR)) allowing normalization of results and sample potency determination. Here we describe the diversity in CALUX response to PCDD/Fs from sediment and soil extracts and not only report the occurrence of superinduction of the CALUX bioassay, but we describe a mechanistically based approach for normalization of superinduction data that results in a more accurate estimation of the relative potency of such sample extracts. Copyright © 2010 Elsevier B.V. All rights reserved.
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From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors.
Liang, Jun; Labadie, Sharada; Zhang, Birong; Ortwine, Daniel F; Patel, Snahel; Vinogradova, Maia; Kiefer, James R; Mauer, Till; Gehling, Victor S; Harmange, Jean-Christophe; Cummings, Richard; Lai, Tommy; Liao, Jiangpeng; Zheng, Xiaoping; Liu, Yichin; Gustafson, Amy; Van der Porten, Erica; Mao, Weifeng; Liederer, Bianca M; Deshmukh, Gauri; An, Le; Ran, Yingqing; Classon, Marie; Trojer, Patrick; Dragovich, Peter S; Murray, Lesley
2017-07-01
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5mg/kg resulted in unbound C max ∼2-fold of its cell potency (PC9 H3K4Me3 0.96μM), meeting our criteria for an in vivo tool compound from a new scaffold. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Efficient elimination of nonstoichiometric enzyme inhibitors from HTS hit lists.
Habig, Michael; Blechschmidt, Anke; Dressler, Sigmar; Hess, Barbara; Patel, Viral; Billich, Andreas; Ostermeier, Christian; Beer, David; Klumpp, Martin
2009-07-01
High-throughput screening often identifies not only specific, stoichiometrically binding inhibitors but also undesired compounds that unspecifically interfere with the targeted activity by nonstoichiometrically binding, unfolding, and/or inactivating proteins. In this study, the effect of such unwanted inhibitors on several different enzyme targets was assessed based on screening results for over a million compounds. In particular, the shift in potency on variation of enzyme concentration was used as a means to identify nonstoichiometric inhibitors among the screening hits. These potency shifts depended on both compound structure and target enzyme. The approach was confirmed by statistical analysis of thousands of dose-response curves, which showed that the potency of competitive and therefore clearly stoichiometric inhibitors was not affected by increasing enzyme concentration. Light-scattering measurements of thermal protein unfolding further verified that compounds that stabilize protein structure by stoichiometric binding show the same potency irrespective of enzyme concentration. In summary, measuring inhibitor IC(50) values at different enzyme concentrations is a simple, cost-effective, and reliable method to identify and eliminate compounds that inhibit a specific target enzyme via nonstoichiometric mechanisms.
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Jeske, Walter P; Hoppensteadt, Debra; Gray, Angel; Walenga, Jeanine M; Cunanan, Josephine; Myers, Lauren; Fareed, Jawed; Bayol, Alain; Rigal, Hélène; Viskov, Christian
2011-10-01
Lower low-molecular-weight heparins are being developed to improve on the safety and efficacy of antithrombotic therapy. Semuloparin and bemiparin are two depolymerized heparins produced by distinct manufacturing processes. The objective of this investigation was to determine whether a common standard could be used to define their potency. Activities were compared using typical clinical coagulation assays and pharmacological assays required for potency assessment. The activity of semuloparin and bemiparin was comparable in FXa-based assays (anti-FXa, Heptest). However, bemiparin produced a stronger effect in the aPTT, ACT and anti-thrombin assays. Assessment of the parallelism of the concentration-response curves indicated that bemiparin and semuloparin are not equivalent in terms of anti-FIIa activity. Bemiparin had a stronger inhibitory effect on thrombin induced platelet aggregation, and a stronger interaction with HIT antibodies. These data demonstrate that depolymerized heparins can exhibit a range of biologic activities making them unique agents. Pharmacopoeial parameters such as anti-IIa and anti-Xa potency and molecular weight are insufficient to characterize such agents. Copyright © 2011 Elsevier Ltd. All rights reserved.
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Potency and stability of frozen urokinase solutions in syringes.
Dedrick, Stephen C; Ramirez-Rico, José
2004-08-01
The stability and potency of frozen urokinase solutions in syringes were studied. To determine the stability and potency of compounded urokinase dilutions after multiple freeze-thaw cycles, a total of 160 syringes containing five urokinase concentrations (2,500, 5,000, 7,500, 12,500, and 25,000 IU/mL) were prepared. For each of the five concentrations tested, two syringes per concentration were reserved for baseline testing. The remaining 150 syringes were frozen at -30 degrees C. After 7 days, half of the syringes (group 1) were thawed at room temperature, tested, and left at room temperature for 12 hours before refreezing. The other half of the syringes (group 2) were kept frozen for 30 days. Thirty days after initial compounding, all syringes were thawed, and the samples' urokinase potency, pH, and physical appearance were evaluated. Syringes were visually inspected for color, clarity, and precipitation. Descriptive statistics were computed for each concentration group and testing day. The compounded dilutions were stable under each experimental condition, with no physical deterioration or loss of in vitro potency after two freeze-thaw cycles. The reduced waste associated with the ability to refreeze unused urokinase could substantially lower the cost of procedures such as thrombolysis after intraventricular hemorrhage and catheter clearance by as much as 95%. Dilutions of urokinase 2,500-25,000 IU/mL were stable in single-use syringes after being frozen for 7 days, thawed, and refrozen for another 23 days.
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Design of potent substrate-analogue inhibitors of canine renin
NASA Technical Reports Server (NTRS)
Hui, K. Y.; Siragy, H. M.; Haber, E.
1992-01-01
Through a systematic study of structure-activity relationships, we designed potent renin inhibitors for use in dog models. In assays against dog plasma renin at neutral pH, we found that, as in previous studies of rat renin inhibitors, the structure at the P2 position appears to be important for potency. The substitution of Val for His at this position increases potency by one order of magnitude. At the P3 position, potency appears to depend on a hydrophobic side chain that does not necessarily have to be aromatic. Our results also support the approach of optimizing potency in a renin inhibitor by introducing a moiety that promotes aqueous solubility (an amino group) at the C-terminus of the substrate analogue. In the design of potent dog plasma renin inhibitors, the influence of the transition-state residue 4(S)-amino-3(S)-hydroxy-5-cyclohexylpentanoic acid (ACHPA)-commonly used as a substitute for the scissile-bond dipeptide to boost potency-is not obvious, and appears to be sequence dependent. The canine renin inhibitor Ac-paF-Pro-Phe-Val-statine-Leu-Phe-paF-NH2 (compound 15; IC50 of 1.7 nM against dog plasma renin at pH 7.4; statine, 4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid; paF, para-aminophenylalanine) had a potent hypotensive effect when infused intravenously into conscious, sodium-depleted, normotensive dogs. Also, compound 15 concurrently inhibited plasma renin activity and had a profound diuretic effect.
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Gokulan, Kuppan; Khare, Sangeeta; Ronning, Donald R; Linthicum, Scott D; Sacchettini, James C; Rupp, Bernhard
2005-07-26
The crystal structures of the murine monoclonal IgG2b(kappa) antibody NC6.8 Fab fragment complexed with high-potency sweetener compound SC45647 and nontasting high-affinity antagonist TES have been determined. The crystal structures show how sweetener potency is fine-tuned by multiple interactions between specific receptor residues and the functionally different groups of the sweeteners. Comparative analysis with the structure of NC6.8 complexed with the super-potency sweetener NC174 reveals that although the same residues in the antigen binding pocket of NC6.8 interact with the zwitterionic, trisubstituted guanidinium sweeteners as well as TES, specific differences exist and provide guidance for the design of new artificial sweeteners. In case of the nonsweetener TES, the interactions with the receptor are indirectly mediated through a hydrogen bonded water network, while the sweeteners bind with high affinity directly to the receptor. The presence of a hydrophobic group interacting with multiple receptor residues as a major determinant for sweet taste has been confirmed. The nature of the hydrophobic group is likely a discriminator for super- versus high-potency sweeteners, which can be exploited in the design of new, highly potent sweetener compounds. Overall similarities and partial conservation of interactions indicate that the NC6.8 Fab surrogate is representing crucial features of the T1R2 taste receptor VFTM binding site.
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Potter, David J; Hammond, Kathy; Tuffnell, Shaun; Walker, Christopher; Di Forti, Marta
2018-04-01
In 2005 and 2008, studies reported that cannabis in England had become dominated by the sinsemilla (unseeded female) form. The average potency (Δ 9 -tetrahydrocannabinol [THC] content) of this material had doubled over the previous decade. Cannabis resin then circulating contained approximately equal ratios of THC and cannabidiol (CBD), whereas sinsemilla was almost devoid of CBD. Despite raised health concerns regarding sinsemilla use and the development of psychotic disorders, no update on street cannabis potency has been published since 2008. A total of 995 seized cannabis samples were acquired from the same 5 constabulary areas included in the 2005 study. The differing forms were segregated, and a representative 460 samples analyzed to assess their cannabinoid content using gas chromatography. The resultant median sinsemilla potency of 14.2% THC was similar to that observed in 2005 (13.9%). In each case, sinsemilla contained minimal CBD. Compared with 2005, resin had significantly higher mean THC (6.3%) and lower CBD (2.3%) contents (p < 0.0001). Although the average THC concentration in sinsemilla samples across the 5 constabularies has remained stable since 2005, the availability of this potent form of cannabis has further increased. Moreover, the now rarer resin samples show significantly decreased CBD contents and CBD:THC ratios, leaving the United Kingdom's cannabis street market populated by high-potency varieties of cannabis, which may have concerning implications for public health. Copyright © 2018 John Wiley & Sons, Ltd.
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Boiret, Mathieu; Meunier, Loïc; Ginot, Yves-Michel
2011-02-20
A near infrared (NIR) method was developed for determination of tablet potency of active pharmaceutical ingredient (API) in a complex coated tablet matrix. The calibration set contained samples from laboratory and production scale batches. The reference values were obtained by high performance liquid chromatography (HPLC) and partial least squares (PLS) regression was used to establish a model. The model was challenged by calculating tablet potency of two external test sets. Root mean square errors of prediction were respectively equal to 2.0% and 2.7%. To use this model with a second spectrometer from the production field, a calibration transfer method called piecewise direct standardisation (PDS) was used. After the transfer, the root mean square error of prediction of the first test set was 2.4% compared to 4.0% without transferring the spectra. A statistical technique using bootstrap of PLS residuals was used to estimate confidence intervals of tablet potency calculations. This method requires an optimised PLS model, selection of the bootstrap number and determination of the risk. In the case of a chemical analysis, the tablet potency value will be included within the confidence interval calculated by the bootstrap method. An easy to use graphical interface was developed to easily determine if the predictions, surrounded by minimum and maximum values, are within the specifications defined by the regulatory organisation. Copyright © 2010 Elsevier B.V. All rights reserved.
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Jálová, V; Jarošová, B; Bláha, L; Giesy, J P; Ocelka, T; Grabic, R; Jurčíková, J; Vrana, B; Hilscherová, K
2013-09-01
Passive and composite sampling in combination with in vitro bioassays and identification and quantification of individual chemicals were applied to characterize pollution by compounds with several specific modes of action in urban area in the basin of two rivers, with 400,000 inhabitants and a variety of industrial activities. Two types of passive samplers, semipermeable membrane devices (SPMD) for hydrophobic contaminants and polar organic chemical integrative samplers (POCIS) for polar compounds such as pesticides and pharmaceuticals, were used to sample wastewater treatment plant (WWTP) influent and effluent as well as rivers upstream and downstream of the urban complex and the WWTP. Compounds with endocrine disruptive potency were detected in river water and WWTP influent and effluent. Year-round, monthly assessment of waste waters by bioassays documented estrogenic, androgenic and dioxin-like potency as well as cytotoxicity in influent waters of the WWTP and allowed characterization of seasonal variability of these biological potentials in waste waters. The WWTP effectively removed cytotoxic compounds, xenoestrogens and xenoandrogens. There was significant variability in treatment efficiency of dioxin-like potency. The study indicates that the WWTP, despite its up-to-date technology, can contribute endocrine disrupting compounds to the river. Riverine samples exhibited dioxin-like, antiestrogenic and antiandrogenic potencies. The study design enabled characterization of effects of the urban complex and the WWTP on the river. Concentrations of PAHs and contaminants and specific biological potencies sampled by POCIS decreased as a function of distance from the city. © 2013.
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Skin sensitisation, vehicle effects and the local lymph node assay.
Basketter, D A; Gerberick, G F; Kimber, I
2001-06-01
Accurate risk assessment in allergic contact dermatitis is dependent on the successful prospective identification of chemicals which possess the ability to behave as skin sensitisers, followed by appropriate measurement of the relative ability to cause sensitisation; their potency. Tools for hazard identification have been available for many years; more recently, a novel approach to the quantitative assessment of potency--the derivation of EC3 values in the local lymph node assay (LLNA)--has been described. It must be recognised, however, that these evaluations of chemical sensitisers also may be affected by the vehicle matrix in which skin exposure occurs. In this article, our knowledge of this area is reviewed and potential mechanisms through which vehicle effects may occur are detailed. Using the LLNA as an example, it is demonstrated that the vehicle may have little impact on the accuracy of basic hazard identification; the data also therefore support the view that testing ingredients in specific product formulations is not warranted for hazard identification purposes. However, the effect on potency estimations is of greater significance. Although not all chemical allergens are affected similarly, for certain substances a greater than 10-fold vehicle-dependent change in potency is observed. Such data are vital for accurate risk assessment. Unfortunately, it does not at present appear possible to predict notionally the effect of the vehicle matrix on skin sensitising potency without recourse to direct testing, for example by estimation of LLNA EC3 data, which provides a valuable tool for this purpose.
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Dielectric dispersion studies of some potentised homeopathic medicines reveal structured vehicle.
Mahata, C R
2013-10-01
Avogadro's Number gives 12c as the limit beyond which no original substance can be present in a highly diluted and succcussed (potentised) homeopathic medicine, implying that chemically such dilutions consist of nothing but the vehicle. But there is evidence that living systems react to homeopathic medicines diluted even above 12c. To explain how such medicines differ from another I hypothesise that altered structure may cause the difference, such as that between diamond and amorphous carbon. Some scientists have argued that dilution followed by succussion may lead to altered structural arrangement of water molecules. This concept may be termed 'Induced Molecular Structure'. Dielectric dispersion studies were conducted in a broad range with potencies below and above the Avogadro limit by taking 6c and 30c potencies of Graphites and Cuprum Metallicum in liquid form. Measurements were made with an Anomalous Dielectric Dispersion Detector (A3D), an instrument developed by the author. Experiments were carried out in a frequency range of 100 kHz to 50 MHz. Shifting of resonance frequencies as a function of medicine and potency, with potencies below and above the Avogadro limit, was observed. The range of resonance frequencies suggest that the phenomenon might originate from oscillation of dipoles caused by electric field in variously structured and polarised water. Also, there is reasonable evidence that frequencies change with materials and potency. Copyright © 2013 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.
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Effects of potentised substances on growth rate of the water plant Lemna gibba L.
Scherr, Claudia; Simon, Meinhard; Spranger, Jörg; Baumgartner, Stephan
2009-04-01
This study investigated, whether the growth rate of Lemna gibba L. (duckweed) can be influenced by the application of homeopathic potencies of gibberellic acid, kinetin, argentum nitricum, and lemna minor. Duckweed was grown in either potencies (14x-30x, decimal steps) or water controls (unsuccussed and succussed) over seven days. Frond (leaf-like structure) growth was measured using a non-destructive image analysis system. Growth rates were calculated for three time intervals (0-7, 0-3, 3-7 days). Five to six independent, randomized and blinded experiments were analysed for each of the four tested substances. Water control experiments were performed repeatedly to test the reliability of the experimental set-up (systematic negative controls). The systematic negative control experiments did not yield any significant effects. Hence, false positive results could be excluded. The test system had a low coefficient of variation (1.5%). Out of the four tested substances gibberellic acid had the most pronounced effect (p=0.0002, F-test) on the main outcome parameter frond growth rate (r(area) day 0-7). Potency levels 15x, 17x, 18x, 23x and 24x reduced growth rate of Lemna gibba (p<0.05 against the pooled water control, LSD test). Lemna gibba may be considered as a suitable test organism for further studies on the efficacy of homeopathic potencies. Evidence accumulates, that adjacent potency levels may strongly differ in their biological activity. Potential consequences for therapeutical application might be worth investigating.
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White, Jessica A; Estrada, Marcus; Weldon, William C; Chumakov, Konstantin; Kouiavskaia, Diana; Fournier-Caruana, Jacqueline; Stevens, Eric; Gary, Howard E; Maes, Edmond F; Oberste, M Steven; Snider, Cynthia J; Anand, Abhijeet; Chen, Dexiang
2018-05-01
According to manufacturers, inactivated poliovirus vaccines (IPVs) are freeze sensitive and require storage between 2°C and 8°C, whereas oral poliovirus vaccine requires storage at -20 °C. Introducing IPV into ongoing immunization services might result in accidental exposure to freezing temperatures and potential loss of vaccine potency. To better understand the effect of freezing IPVs, samples of single-dose vaccine vials from Statens Serum Institut (VeroPol) and multi-dose vaccine vials from Sanofi Pasteur (IPOL) were exposed to freezing temperatures mimicking what a vaccine vial might encounter in the field. D-antigen content was measured to determine the in vitro potency by ELISA. Immunogenicity testing was conducted for a subset of exposed IPVs using the rat model. Freezing VeroPol had no detectable effect on in vitro potency (D-antigen content) in all exposures tested. Freezing of the IPOL vaccine for 7 days at -20 °C showed statistically significant decreases in D-antigen content by ELISA in poliovirus type 1 (p < 0.0001) and type 3 (p = 0.048). Reduction of poliovirus type 2 potency also approached significance (p = 0.062). The observed loss in D-antigen content did not affect immunogenicity in the rat model. Further work is required to determine the significance of the loss observed and the implications for vaccine handling policies and practices. Copyright © 2018. Published by Elsevier Ltd.
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Janson, Juliette; Eketjäll, Susanna; Tunblad, Karin; Jeppsson, Fredrik; Von Berg, Stefan; Niva, Camilla; Radesäter, Ann-Cathrin; Fälting, Johanna; Visser, Sandra A G
2014-03-01
The aims were to quantify the in vivo time-course between the oral dose, the plasma and brain exposure and the inhibitory effect on Amyloid β (Aβ) in brain and cerebrospinal fluid, and to establish the correlation between in vitro and in vivo potency of novel β-secretase (BACE1) inhibitors. BACE1-mediated inhibition of Aβ was quantified in in vivo dose- and/or time-response studies and in vitro in SH-SY5Y cells, N2A cells, and primary cortical neurons (PCN). An indirect response model with inhibition on Aβ production rate was used to estimate unbound in vivo IC 50 in a population pharmacokinetic-pharmacodynamic modeling approach. Estimated in vivo inhibitory potencies varied between 1 and 1,000 nM. The turnover half-life of Aβ40 in brain was predicted to be 0.5 h in mouse and 1 h in guinea pig. An excellent correlation between PCN and in vivo potency was observed. Moreover, a strong correlation in potency was found between human SH-SY5Y cells and mouse PCN, being 4.5-fold larger in SH-SY5Y cells. The strong in vivo-in vitro correlation increased the confidence in using human cell lines for screening and optimization of BACE1 inhibitors. This can optimize the design and reduce the number of preclinical in vivo effect studies.
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Korf, Dirk J; Benschop, Annemieke; Wouters, Marije
2007-05-01
To determine whether a classification of cannabis users into different types can help to clarify the relationship between cannabis potency and consumption behaviour, harmful physical effects and psychological dependency. A field sample of 388 respondents was recruited who had smoked cannabis at least once in the past month. They were contacted and interviewed in 28 cannabis coffee shops located in five Dutch cities. Data were collected with an assisted self-completion questionnaire. Cluster analysis was performed using the k-means method. Various ways were observed in which cannabis users in natural settings adjusted their intake to the potency of the drug. Cluster analysis identified three broad types of cannabis users. The strongest high type was the youngest, consumed the highest monthly dose, inhaled higher-potency cannabis more deeply, and scored highest on psychological cannabis dependency. The consistent high type preferred milder cannabis, consumed the lowest monthly dose, and compensated for stronger cannabis by inhaling less deeply and smoking less. The steady quantity type was the oldest, usually smoked alone, consumed an intermediate monthly dose, and did not tend to adjust the depth of inhalation to the potency of the cannabis. The results suggest that this typology might also reflect three successive stages in the careers of continuing cannabis users. Laboratory studies to assess the effects of higher THC concentrations on external and internal exposure to cannabis should allow for the possibility that the types of users studied can affect the results.
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Quantitative relationship between the local lymph node assay and human skin sensitization assays.
Schneider, K; Akkan, Z
2004-06-01
The local lymph node assay (LLNA) is a new test method which allows for the quantitative assessment of sensitizing potency in the mouse. Here, we investigate the quantitative correlation between results from the LLNA and two human sensitization tests--specifically, human repeat insult patch tests (HRIPTs) and human maximization tests (HMTs). Data for 57 substances were evaluated, of which 46 showed skin sensitizing properties in human tests, whereas 11 yielded negative results in humans. For better comparability data from mouse and human tests were transformed to applied doses per skin area, which ranged over four orders of magnitude for the substances considered. Regression analysis for the 46 human sensitizing substances revealed a significant positive correlation between the LLNA and human tests. The correlation was better between LLNA and HRIPT data (n=23; r=0.77) than between LLNA and HMT data (n=38; r=0.65). The observed scattering of data points is related to various uncertainties, in part associated with insufficiencies of data from older HMT studies. Predominantly negative results in the LLNA for another 11 substances which showed no skin sensitizing activity in human maximization tests further corroborate the correspondence between LLNA and human tests. Based on this analysis, the LLNA can be considered a reliable basis for relative potency assessments for skin sensitizers. Proposals are made for the regulatory exploitation of the LLNA: four potency groups can be established, and assignment of substances to these groups according to the outcome of the LLNA can be used to characterize skin sensitizing potency in substance-specific assessments. Moreover, based on these potency groups, a more adequate consideration of sensitizing substances in preparations becomes possible. It is proposed to replace the current single concentration limit for skin sensitizers in preparations, which leads to an all or nothing classification of a preparation as sensitizing to skin ("R43") in the European Union, by differentiated concentration limits derived from the limits for the four potency groups.
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Freeman, Tom P; Morgan, Celia J A; Hindocha, Chandni; Schafer, Gráinne; Das, Ravi K; Curran, H Valerie
2014-10-01
(1) To determine whether measured concentrations of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in individuals' own cannabis predict their estimates of drug potency and actual titration; and (2) to ascertain if these effects are influenced by frequency of use and cannabis type. Cross-sectional, naturalistic. Participants' own homes. A total of 247 cannabis users in the United Kingdom: 152 'recreational' (1-24 days/month) and 95 'daily' (≥25 days/month). Participants rated their own cannabis for its potency (1-10) and type ('resin', 'herbal', 'skunk') before smoking it in front of the researcher. The amount of cannabis (g) used in their joints was recorded and an additional sample was analysed for THC and CBD concentrations (%). THC concentrations were related negatively to the amount of cannabis used [unstandardized regression coefficient: b = -0.009, 95% confidence interval (CI) = -0.017, -0.002]. Potency estimates were predicted by increasing THC (b = 0.055, 95% CI = 0.020, 0.090) and decreasing CBD (b = -0.160, 95% CI = -0.284, -0.062), and both of these associations were mediated by cannabis type (THC: b = 0.018, 95% CI = 0.006, 0.037; CBD: b = -0.105, 95% CI = -0.198, -0.028). Potency estimates were more reflective of THC as frequency of use increased (b = 0.004, 95% CI = 0.001, 0.007) and were 7.3 times more so in daily (partial r = 0.381) than recreational users (r = 0.052). When using their own cannabis in a naturalistic setting, people titrate the amount they roll in joints according to concentrations of delta-9-tetrahydrocannabinol (THC) but not cannabidiol (CBD). Recreational users thus show poor understanding of cannabis potency. © 2014 Society for the Study of Addiction.
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Dorey, L; Hobson, S; Lees, P
2017-10-01
The pharmacodynamics of oxytetracycline was determined for pig respiratory tract pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Indices of potency were determined for the following: (i) two matrices, broth and pig serum; (ii) five overlapping sets of twofold dilutions; and (iii) a high strength starting culture. For A. pleuropneumoniae, minimum inhibitory concentration (MIC) was similar for the two matrices, but for P. multocida, differences were marked and significantly different. MIC and minimum bactericidal concentration (MBC) serum: broth ratios for A. pleuropneumoniae were 0.83:1 and 1.22:1, respectively, and corresponding values for P. multocida were 22.0:1 and 7.34:1. For mutant prevention concentration (MPC) serum: broth ratios were 0.79:1 (A. pleuropneumoniae) and 20.9:1 (P. multocida). These ratios were corrected for serum protein binding to yield fraction unbound (fu) serum: broth MIC ratios of 0.24:1 (A. pleuropneumoniae) and 6.30:1 (P. multocida). Corresponding fu serum: broth ratios for MPC were almost identical, 0.23:1 and 6.08:1. These corrections for protein binding did not account for potency differences between serum and broth for either species; based on fu serum MICs, potency in serum was approximately fourfold greater than predicted for A. pleuropneumoniae and sixfold smaller than predicted for P. multocida. For both broth and serum and both bacterial species, MICs were also dependent on initial inoculum strength. The killing action of oxytetracycline had the characteristics of codependency for both A. pleuropneumoniae and P. multocida in both growth media. The in vitro potency of oxytetracycline in pig serum is likely to be closer to the in vivo plasma/serum concentration required for efficacy than potency estimated in broths. © 2017 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.
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Validation of self-reported cannabis dose and potency: an ecological study.
van der Pol, Peggy; Liebregts, Nienke; de Graaf, Ron; Korf, Dirk J; van den Brink, Wim; van Laar, Margriet
2013-10-01
To assess the reliability and validity of self-reported cannabis dose and potency measures. Cross-sectional study comparing self-reports with objective measures of amount of cannabis and delta-9-tetrahydrocannabinol (THC) concentration. Ecological study with assessments at participants' homes or in a coffee shop. Young adult frequent cannabis users (n = 106) from the Dutch Cannabis Dependence (CanDep) study. The objectively measured amount of cannabis per joint (dose in grams) was compared with self-reported estimates using a prompt card and average number of joints made from 1 g of cannabis. In addition, objectively assessed THC concentration in the participant's cannabis was compared with self-reported level of intoxication, subjective estimate of cannabis potency and price per gram of cannabis. Objective estimates of doses per joint (0.07-0.88 g/joint) and cannabis potency (1.1-24.7%) varied widely. Self-reported measures of dose were imprecise, but at group level, average dose per joint was estimated accurately with the number of joints made from 1 g [limit of agreement (LOA) = -0.02 g, 95% confidence interval (CI) = -0.29; 0.26], whereas the prompt card resulted in serious underestimation (LOA = 0.14 g, 95% CI = -0.10; 0.37). THC concentration in cannabis was associated with subjective potency ['average' 3.77% (P = 0.002) and '(very) strong' 5.13% more THC (P < 0.001) than '(very) mild' cannabis] and with cannabis price (about 1% increase in THC concentration per euro spent on 1 g of cannabis, P < 0.001), but not with level of intoxication. Self-report measures relating to cannabis use appear at best to be associated weakly with objective measures. Of the self-report measures, number of joints per gram, cannabis price and subjective potency have at least some validity. © 2013 Society for the Study of Addiction.
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Sameshima, H; Omori, M; Nishimura, Y; Chihaya, Y; Itoh, F; Mizushima, Y; Yabuuchi, K; Ohno, K; Furukawa, H; Yoshida, I; Ueno, M; Yahara, I; Kato, I
2001-05-01
Cefmatilen hydrochloride hydrate (S-1090) was orally administered to rats at dose levels of 100, 300 and 1000 mg potency/kg once daily for 6 months. All the S-1090 treated groups showed soft feces, reddish-brown feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet), abdominal distention, increased food and water consumption, lower urine pH, and a decrease of white blood cells counts (except for males of the 100 mg potency/kg group). One male in the 300 mg potency/kg group showed mucous feces and marked decrease in body weight, and diet in the middle stage of the administration period. In necropsy of the survivors of all treated groups, marked cecal enlargement was noted. No remarkable changes were observed in the other examination items. From the early stage of the withdrawal period, animals in the 1000 mg potency/kg group showed again soft or mucous feces and a marked decrease in body weight. Of these animals, one male died and another male was sacrificed in a moribund state at about 2 weeks of the withdrawal period. Enterocolitis was observed in these cases. Almost all animals recovered within 3 weeks of withdrawal. A supplemental study of the 6-month toxicity study was conducted to examine the mechanisms of enterocolitis and the changes observable in the 100 or 300 mg potency/kg groups after drug withdrawal. As a reference, cefdinir (CFDN), an oral cephem antibiotic the same as S-1090, was added in the 1000 mg potency/kg group. No deaths occurred in any groups. Decreased intestinal flora were noted in all the groups treated with S-1090 or CFDN at the end of the dosing period. At 2 weeks of the withdrawal period, C. difficile and its D-1 toxin in the cecal contents were highly detected in the S-1090 300 and 1000 mg potency/kg groups and CFDN group. Inflammatory changes in the cecum and colon were observed in these groups. At 4 weeks of the withdrawal period, intestinal flora in the S-1090 groups almost returned to the condition before dosing, but those in the CFDN group were retained highly. Cecal D-1 toxin in the CFDN group was positive and higher than in the S-1090 groups. It was thus considered that the critical condition with enterocolitis resulted from C. difficile, which proliferated more rapidly than the other bacteria and D-1 toxin produced by this bacteria in the withdrawal period. Above changes were commonly observed in the CFDN group. The NOAEL of S-1090 was assessed to be 100 mg potency/kg/day which induced no enteritis.
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2C-I-NBOMe, an "N-bomb" that kills with "Smiles". Toxicological and legislative aspects.
Nikolaou, Panagiota; Papoutsis, Ioannis; Stefanidou, Maria; Spiliopoulou, Chara; Athanaselis, Sotiris
2015-01-01
Substituted phenethylamines are a class of designer drugs that have recently emerged in the drug abuse market. Such substances remain legal to use, possess, and supply until these compounds become classified as scheduled. 2C-I-NBOMe or 25I-NBOMe is the N-benzyl-derivative of the iodo-substituted dimethoxy-phenethylamine (2C-I) that appeared recently in the drug market under the street name "N-Bomb". Due to its high potency, intoxications and fatal cases related to 2C-I-NBOMe use are increased worldwide. The use and trafficking of this substituted phenethylamine is banned only in some countries. A comprehensive review was performed using PubMed and Medline databases, together with additional non-peer reviewed information sources, including books and publications of state authorities in different countries, regarding chemistry, availability, pharmacology, and toxicology of 2C-I-NBOMe. Intoxications or lethal cases, published or reported, as well as the current legislation on this newly introduced drug are also reviewed.
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Zhang, Yiqian; Yu, Jiahui; Zhang, Wen; Wang, Yuewei; He, Yi; Zhou, Shuiping; Fan, Guanwei; Yang, Hua; Zhu, Yan; Li, Ping
2018-06-12
Qishen Yiqi is a widely used Chinese herbal medicine formula with "qi invigorating and blood activating" property. Its dripping pill preparation (QSYQ) is a commercial herbal medicine approved by the China Food and Drug Administration (CFDA) in 2003 and is extensively used clinically to treat cardiovascular diseases, such as ischemic heart failure and angina pectoris, as well as for the secondary prevention of myocardial infarction. However, the bioactive ingredients of QSYQ remain unclear. As QSYQ is a compound herbal formula, it is of great importance to elucidate its pharmacologically active ingredients and underlying synergetic effects. This experimental study was conducted to comprehensively determine the combinatorial bioactive ingredients (CBIs) in QSYQ and to elucidate their potential synergetic effects. The established strategy may shed new light on how to rapidly determine CBIs in complex herbal formulas with holistic properties. An integrated evidence-based targeting strategy was introduced and validated to determine CBIs in QSYQ. The strategy included the following steps: (1) Chemical ingredients in QSYQ were analyzed via UPLC-Q-TOF/MS in the negative and positive modes and were identified by comparison with standard compounds and previously reported data. Their potential therapeutic activities were predicted based on the ChEMBL database to preliminarily search for candidate bioactive ingredients, and their combination was defined as the CBIs. (2) The CBIs were directly trapped and prepared from QSYQ with a two-dimensional chromatographic separation system, and the remaining part was defined as the rest ingredients (RIs). (3) As animal and cell models, left anterior descending coronary artery ligation (LAD)-induced heart failure in rats and hypoxia-induced cardiac myocyte injury in H9c2 cells were applied to compare the potency of QSYQ, CBIs and RIs. (4) The synergetic effects on cardiac myocyte protection of multiple ingredients in CBIs were examined in this cell model. (1) Forty-three ingredients in QSYQ were identified via UPLC-Q-TOF/MS. Based on evidence-based screening using the ChEMBL database, 24 ingredients were predicted to be bioactive ingredients, and their combination was considered the CBIs. (2) The CBIs and RIs were successfully prepared according to a two-dimensional chromatographic system. The CBIs were directly trapped and knocked out from QSYQ by hydrophilic interaction liquid chromatography coupled with reverse-phase liquid chromatography. The remaining part was used as RIs. (3) The results from pharmacological evaluation revealed that CBIs and QSYQ, but not RIs, significantly prevented myocardium injury; improved the ejection fraction (EF) and fractional shortening (FS); decreased the release of cardiac enzymes, including CK, CK-MB, and LDH; alleviated mitochondrial dysfunction; and protected the cell nucleus number and mitochondrial mass. Furthermore, QSYQ and CBIs possessed similar potency. (4) In hypoxia-stimulated H9c2 cells, CBIs showed far greater potency regarding the protection of cardiac myocyte injury than the individual ingredients in QSYQ, exhibiting obvious synergetic effects. An integrated evidence-based targeting strategy was successfully established and validated to determine CBIs from QSYQ with excellent efficiency. Importantly, the holistic property of QSYQ was retained in the CBIs. Hence, this study may shed new light on how to rapidly reveal combinatorial bioactive ingredients from complex prescriptions and will be greatly helpful in the establishment of an appropriate approach to quality control for herbal medicines. Copyright © 2018 Elsevier B.V. All rights reserved.
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Cytotoxicity and Cell Signaling in MH-S Cells: Relative Potency of Diesel and Coal Combustion Particles P. Singh1, Y. Kostetski2, M. Daniels1, T. Stevens3 and MI Gilmour 1USEPA, RTP, NC, 2National University of Singapore, Singapore, 3University of North Carolina, Chapel Hill, NC<...
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ABSTRACT Results of global gene expression profiling after short-term exposures can be used to inform tumorigenic potency and chemical mode of action (MOA) and thus serve as a strategy to prioritize future or data-poor chemicals for further evaluation. This compilation of cas...
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Stigma Sentiments and Self-Meanings: Exploring the Modified Labeling Theory of Mental Illness
ERIC Educational Resources Information Center
Kroska, Amy; Harkness, Sarah K.
2006-01-01
We introduce "stigma sentiments" as a way to operationalize the cultural conceptions of the mentally ill. Stigma sentiments are the evaluation, potency, and activity (EPA) associated with the cultural category "a mentally ill person." We find consistent support for the validity of the evaluation and potency components as measures of these…
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Kelli Hoover; Merideth A. Humphries; Alyssa R. Genfron; James M. Slavicek
2010-01-01
Enhancins are metalloproteases found in many betabaculoviruses and several alphabaculoviruses, which enhance alphabaculovirus potency by degrading a protein component of the peritrophic matrix (PM), facilitating passage of virions through this structure. Earlier studies on betabaculovirus enhancins within heterologous systems suggested that enhancins facilitate virion...
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THE INFLUENCE OF SERUM BINDING PROTEINS AND CLEARANCE ON THE COMPARATIVE RECEPTOR BINDING POTENCY OF ENDOCRINE ACTIVE COMPOUNDS. JG Teeguarden1 and HA Barton2. 1ENVIRON International, Ruston LA; 2US EPA, ORD, NHEERL, ETD, Pharmacokinetics Branch, RTP, NC.
One measure of th... -
THE INFLUENCE OF SERUM BINDING PROTEINS ON THE COMPARATIVE RECEPTOR BINDING POTENCY OF ENDOCRINE ACTIVE COMPOUNDS. JG Teeguarden1 and HA Barton2. 1ICF Consulting, Research Triangle Park NC; 2US EPA, ORD, NHEERL, ETD, Pharmacokinetics Branch, RTP, NC.
Accurate comparison of... -
Tewari, Ashutosh K; Ali, Adnan; Metgud, Sheela; Theckumparampil, Nithin; Srivastava, Abhishek; Khani, Francesca; Robinson, Brian D; Gumpeni, Naveen; Shevchuk, Maria M; Durand, Matthieu; Sooriakumaran, Prasanna; Li, Jinyi; Leung, Robert; Peyser, Alexandra; Gruschow, Siobhan; Asija, Vinita; Harneja, Niyati
2013-06-01
To report our unique approach for individualizing robotic prostate cancer surgery by risk stratification and sub classification of the periprostatic space into 4 distinct compartments, and thus performing 4 precise different grades of nerve sparing based on neurosurgical principles and to present updated potency and continence outcomes data of patients undergoing robotic-assisted laparoscopic prostatectomy (RALP) using our risk-stratified approach based on layers of periprostatic fascial dissection. (1) Between January 2005 and December 2010, 2,536 men underwent RALP by a single surgeon at our institution. (2) Included patients were those with ≥ 1-year follow-up and were preoperatively continent and potent, defined as having a SHIM questionnaire score of >21; thus, the final number of patient in the study cohort was 1,335. (3) Postoperative potency was defined as the ability to have successful intercourse (score of ≥ 4 on question 2 of the SHIM); continence was defined as the use of no pads per 24 h. (1) The potency and continence for NS grades 1, 2, 3, and 4 were found to be 90.6, 76.2, 60.5, and 57.1 % (P < 0.001) and 98, 93.2, 90.1, and 88.9 % (P < 0.001), respectively. (2) The overall PSM rates for patients with NS grades 1, 2, 3, and 4 were 10.5, 7, 5.8, and 4.8 %, respectively (P = 0.064). The study found a correlation between risk-stratified grades of NS technique and continence and potency. Patients with lesser grades of NS had higher rates of potency and continence.
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Chan, Gary C K; Hall, Wayne; Freeman, Tom P; Ferris, Jason; Kelly, Adrian B; Winstock, Adam
2017-09-01
Recent reports suggest an increase in use of extremely potent cannabis concentrates such as Butane Hash Oil (BHO) in some developed countries. The aims of this study were to examine the characteristics of BHO users and the effect profiles of BHO. Anonymous online survey in over 20 countries in 2014 and 2015. Participants aged 18 years or older were recruited through onward promotion and online social networks. The overall sample size was 181,870. In this sample, 46% (N=83,867) reported using some form of cannabis in the past year, and 3% reported BHO use (n=5922). Participants reported their use of 7 types of cannabis in the past 12 months, the source of their cannabis, reasons for use, use of other illegal substances, and lifetime diagnosis for depression, anxiety and psychosis. Participants were asked to rate subjective effects of BHO and high potency herbal cannabis. Participants who reported a lifetime diagnosis of depression (OR=1.15, p=0.003), anxiety (OR=1.72, p<0.001), and a larger number of substance use (OR=1.29, p<0.001) were more likely to use BHO than only using high potency herbal cannabis. BHO users also reported stronger negative effects and less positive effects when using BHO than high potency herbal cannabis (p<0.001) CONCLUSION: Mental health problems and other illicit drug use were associated with use of BHO. BHO was reported to have stronger negative and weaker positive effects than high potency herbal cannabis. Copyright © 2017. Published by Elsevier B.V.
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In vivo potency of different ligands on voltage-gated sodium channels.
Safrany-Fark, Arpad; Petrovszki, Zita; Kekesi, Gabriella; Liszli, Peter; Benedek, Gyorgy; Keresztes, Csilla; Horvath, Gyongyi
2015-09-05
The Ranvier nodes of thick myelinated nerve fibers contain almost exclusively voltage-gated sodium channels (Navs), while the unmyelinated fibers have several receptors (e.g., cannabinoid, transient receptor potential vanilloid receptor 1), too. Therefore, a nerve which contains only motor fibers can be an appropriate in vivo model for selective influence of Navs. The goals were to evaluate the potency of local anesthetic drugs on such a nerve in vivo; furthermore, to investigate the effects of ligands with different structures (arachidonic acid, anandamide, capsaicin and nisoxetine) that were proved to inhibit Navs in vitro with antinociceptive properties. The marginal mandibular branch of the facial nerve was explored in anesthetized Wistar rats; after its stimulation, the electrical activity of the vibrissae muscles was registered following the perineural injection of different drugs. Lidocaine, bupivacaine and ropivacaine evoked dose-dependent decrease in electromyographic activity, i.e., lidocaine had lower potency than bupivacaine or ropivacaine. QX-314 did not cause any effect by itself, but its co-application with lidocaine produced a prolonged inhibition. Nisoxetine had a very low potency. While anandamide and capsaicin in high doses caused about 50% decrease in the amplitude of action potential, arachidonic acid did not influence the responses. We proved that the classical local anesthetics have high potency on motor nerves, suggesting that this method might be a reliable model for selective targeting of Navs in vivo circumstances. It is proposed that the effects of these endogenous lipids and capsaicin on sensory fibers are not primarily mediated by Navs. Copyright © 2015 Elsevier B.V. All rights reserved.
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New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition.
Peletier, Lambertus A; Gabrielsson, Johan
2018-05-14
In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be useful for small molecule interactions with extravascularly located targets. Including target turnover, ligand-target complex kinetics and binding properties in expressions of potency and efficacy will improve our understanding of within and between-individual (and across species) variability. The new expressions of potencies highlight the fact that the level of drug-induced target suppression is very much governed by target turnover properties rather than by the target expression level as such.
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Efficacy and safety of tranexamic acid as an emetic in dogs.
Kakiuchi, Hitoshi; Kawarai-Shimamura, Asako; Fujii, Yoko; Aoki, Takuma; Yoshiike, Masaki; Arai, Hayato; Nakamura, Atsushi; Orito, Kensuke
2014-12-01
To determine dose dependency of tranexamic acid-induced emesis and the time course of the antifibrinolytic potency of tranexamic acid in dogs. 10 Beagles. In a dose-escalating experiment, ascending doses of tranexamic acid (10, 20, and 30 mg/kg, IV) were administered at 5-minute intervals until vomiting was observed. In a separate single-dose experiment, ascending doses of tranexamic acid (20, 30, 40, and 50 mg/kg, IV) were administered at 1-week intervals until vomiting was observed. Time to onset of vomiting and number of vomiting episodes were measured in both experiments. In a coagulation experiment, a single 50 mg/kg bolus of tranexamic acid was administered, and blood was obtained 1 hour before and 20 minutes, 3 hours, and 24 hours after administration. Antifibrinolytic potency of tranexamic acid was evaluated by use of a modified rotational thromboelastography method. Tranexamic acid induced vomiting in a dose-dependent manner. Vomiting frequency was ≤ 2 episodes, and vomiting concluded ≤ 250 seconds after administration. Antifibrinolytic potency of tranexamic acid was significantly higher at 20 minutes following administration, but not different by 24 hours, when compared with the potency measured before administration. No adverse effects were observed in any experiment. IV administration of tranexamic acid induced emesis in a dose-dependent manner. The antifibrinolytic potency of tranexamic acid decreased in a time-dependent manner and was resolved ≤ 24 hours after administration. Further studies are warranted to investigate the emetic and other adverse effects of tranexamic acid in dogs of various breeds and ages.
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Choline as an agonist: determination of its agonistic potency on cholinergic receptors.
Ulus, I H; Millington, W R; Buyukuysal, R L; Kiran, B K
1988-07-15
These experiments examined the potency of choline as a cholinergic agonist at both muscarinic and nicotinic receptors in rat brain and peripheral tissues. Choline stimulated the contraction of isolated smooth muscle preparations of the stomach fundus, urinary bladder and trachea and reduced the frequency of spontaneous contractions of the right atrium at high micromolar and low millimolar concentrations. The potency of choline to elicit a biological response varied markedly among these tissues; EC50 values ranged between 0.41 mM in the fundus to 14.45 mM in the atrium. Choline also displaced [3H]quinuclidinyl benzilate binding in a concentration-dependent manner although, again, its potency varied among different brain regions (Ki = 1.2 to 3.5 mM) and peripheral tissues (Ki = 0.28 to 3.00 mM). Choline exhibited a comparable affinity for nicotinic receptors. It stimulated catecholamine release from the vascularly perfused adrenal gland (EC50 = 1.3 mM) and displaced L-[3H]nicotine binding to membrane preparations of brain and peripheral tissues (Ki = 0.38 to 1.17 mM). However, the concentration of choline required to bind to cholinergic receptors in most tissues was considerably higher than serum levels either in controls (8-13 microM) or following the administration of choline chloride (200 microM). These results clearly demonstrate that choline is a weak cholinergic agonist. Its potency is too low to account for the central nervous system effects produced by choline administration, although the direct activation of cholinergic receptors in several peripheral tissues may explain some of its side effects.
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Schuhmacher, S; Schulz, E; Oelze, M; König, A; Roegler, C; Lange, K; Sydow, L; Kawamoto, T; Wenzel, P; Münzel, T; Lehmann, J; Daiber, A
2009-09-01
The chronic use of organic nitrates is limited by serious side effects including oxidative stress, nitrate tolerance and/or endothelial dysfunction. The side effects and potency of nitroglycerine depend on mitochondrial aldehyde dehydrogenase (ALDH-2). We sought to determine whether this concept can be extended to a new class of organic nitrates with amino moieties (aminoalkyl nitrates). Vasodilator potency of the organic nitrates, in vitro tolerance and in vivo tolerance (after continuous infusion for 3 days) were assessed in wild-type and ALDH-2 knockout mice by isometric tension studies. Mitochondrial oxidative stress was analysed by L-012-dependent chemiluminescence and protein tyrosine nitration. Aminoethyl nitrate (AEN) showed an almost similar potency to glyceryl trinitrate (GTN), even though it is only a mononitrate. AEN-dependent vasodilatation was mediated by cGMP and nitric oxide. In contrast to triethanolamine trinitrate (TEAN) and GTN, AEN bioactivation did not depend on ALDH-2 and caused no in vitro tolerance. In vivo treatment with TEAN and GTN, but not with AEN, induced cross-tolerance to acetylcholine (ACh)-dependent and GTN-dependent relaxation. Although all nitrates tested induced tolerance to themselves, only TEAN and GTN significantly increased mitochondrial oxidative stress in vitro and in vivo. The present results demonstrate that not all high potency nitrates are bioactivated by ALDH-2 and that high potency of a given nitrate is not necessarily associated with induction of oxidative stress or nitrate tolerance. Obviously, there are distinct pathways for bioactivation of organic nitrates, which for AEN may involve xanthine oxidoreductase rather than P450 enzymes.
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[Potency testing of anti-lymphocyte Globulins: In vitro alternatives for the monkey skin-graft assay
Conrad, Christoph; Kabelitz, Dieter; Schäffner, Gabriele
1998-01-01
Antilymphocyte globulins (ALG) are immunosuppressive agents of animal origin currently used in clinical transplantation medicine and for the treatment of severe aplastic anemia. The potency of each batch is tested in vivo using primates as hosts for allogeneic skin transplantation. The test is done with a maximum of three animals, one as a control and two after the treatment with ALG. The two in vitro methods in use are a cytotoxic assay and the rosette inhibition assay. These methods are evaluated with the microscope. Besides wellfare aspects these methods require a lot of experience, are subjective, difficult to validate and the information about the biological potency of the sera is questionable. The aim of our study is a better biological characterisation as a prerequisite to subsequently define an in vitro alternative for the potency test in monkeys. Using a competition assay with monoclonal antibodies we can identify several specificities directed against functional molecules on T cells (e.g., CD2, CD3, CD5, CD28), B Cells (CD19), macrophages and natural killer cells (CD16) and nonlineage specificities such as CD18, CD25, CD29, CD95. This method could describe a part of the biological potency and control homogeneity of batches. The cytotoxic capacity of ALG either with or without complement as well as DNA-fragmentation characteristic for apoptosis can be analysed by flowcytometry using propidiumiodide- (PI) incorporation. Immunoprecipitation of cell-lysate with ALG
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Liquid carbon dioxide of magmatic origin and its role in volcanic eruptions
Chivas, A.R.; Barnes, I.; Evans, William C.; Lupton, J.E.; Stone, J.O.
1987-01-01
Natural liquid carbon dioxide is produced commercially from a 2.5-km-deep well near the 4,500-yr-old maar volcano, Mount Gambier, South Australia. The carbon dioxide has accumulated in a dome that is located on the extension of a linear chain of volcanic activity. A magmatic origin for the fluid is suggested by the geological setting, ??13CPDB of -4.0???, for the CO2 (where PDB represents the carbon-isotope standard), and a relatively high 3He component of the contained helium and high 3He/C ratio (6.4 x 10-10). The 3He/ 4He and He/Ne ratios are 3.0 and > 1,370 times those of air, respectively. The CO2, as collected at the Earth's surface at 29.5 ??C and 75 bar, expands more than 300-fold to form a gas at 1 atm and 22 ??C. We suggest that liquid CO2 or high-density CO2 fluid (the critical point is 31.1 ??C, 73.9 bar) of volcanic origin that expands explosively from shallow levels in the Earth's crust may be a major contributor to 'phreatic' volcanic eruptions and maar formation. Less violent release of magmatic CO2 into crater lakes may cause gas bursts with equally disastrous consequences such as occurred at Lake Nyos, Cameroon, in August 1986. ?? 1987 Nature Publishing Group.
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NASA Astrophysics Data System (ADS)
Zhu, Shifa; Yue, Hui; Zhu, Xiaomin; Sun, Shuyang; Wei, Wei; Liu, Xin; Jia, Ye
2017-05-01
Dolomitization of fine-grained volcaniclastic rocks is common in the Lower Cretaceous of the A'nan Sag in the Er'lian Basin of China. Analysis of core samples shows that the organic-rich volcaniclastic rocks are mainly composed of reworked felsic volcanic materials and terrigenous clay minerals. The fine-grained volcaniclastic rocks can be divided into four types: volcaniclastic rocks without carbonatization, volcaniclastic rocks with ferroan dolomites, dolomitized and calcified volcaniclastic rocks, and calcified volcaniclastic rocks. The parent rocks of the volcaniclastic rocks have high silicon and potassium contents and low iron and magnesium contents, and are probably felsic magma of the calc-alkaline series. The average values of δ13CPDB of the carbonate minerals are about 3.13‰; the average values of δ18OPDB are about - 16.74‰. The compositions of C and O isotopes are probably influenced by bacterial methanogenesis. Iron, magnesium, and calcium are probably derived from illitization of terrigenous smectite. A model for dolomitization of felsic volcaniclastic rock is proposed, including three stages: 1) mixed sedimentation and bacterial methanogenesis (< 75 °C); 2) transformation of clay minerals (> 70 °C) and dolomitization (75 to 97 °C); and 3) dissolution. Late dissolution of authigenic carbonate minerals, creating abundant secondary pores, is significant for hydrocarbon accumulation.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Cao, Bin; Shi, Liang; Brown, Roslyn N.
This study characterizes the composition of extracellular polymeric substances (EPS) from Shewanella sp. HRCR-1 biofilms to provide insight into potential interactions of EPS with redox-active metals and radionuclides. Both bound and loosely associated EPS were extracted from Shewanella sp. HRCR-1 biofilms prepared using a hollow-fiber membrane biofilm reactor (HfMBR). FTIR spectra revealed the presence of proteins, polysaccharides, nucleic acids, membrane lipids, and fatty acids in both bound and loosely associated EPS. Using a global proteomic approach, a total of 58 extracellular and outer membrane proteins were identified in the EPS. These included homologues of multiple S. oneidensis MR-1 proteins thatmore » potentially contribute to key physiological biofilm processes, such as biofilm-promoting protein BpfA, surface-associated serine protease, nucleotidases (CpdB and UshA), an extracellular lipase, and oligopeptidases (PtrB and a M13 family oligopeptidase lipoprotein). In addition, 20 redox proteins were found in extracted EPS. Among the detected redox proteins were the homologues of two S. oneidensis MR-1 c-type cytochromes, MtrC and OmcA, which have been implicated in extracellular electron transfer. Given their detection in the EPS of Shewanella sp. HRCR 1 biofilms, c-type cytochromes may contribute to the possible redox activity of the biofilm matrix and play important roles in extracellular electron transfer reactions.« less
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van den Berg, Martin; Birnbaum, Linda S.; Denison, Michael; De Vito, Mike; Farland, William; Feeley, Mark; Fiedler, Heidelore; Hakansson, Helen; Hanberg, Annika; Haws, Laurie; Rose, Martin; Safe, Stephen; Schrenk, Dieter; Tohyama, Chiharu; Tritscher, Angelika; Tuomisto, Jouko; Tysklind, Mats; Walker, Nigel; Peterson, Richard E.
2007-01-01
In June 2005 a WHO-IPCS expert meeting was held in Geneva during which the toxic equivalency factors (TEFs) for dioxin like compounds, including some polychlorinated biphenyls (PCBs), were re-evaluated. For this re-evaluation process the refined TEF database recently published by Haws and coworkers (Toxicol. Sci. 2006, 89:4-30) was used as a starting point. Decisions about a TEF value were made based on a combination of unweighted relative effect potency (REP) distributions from this database, expert judgement and point estimates. Previous TEFs were assigned in increments of 0.01, 0.05, 0.1, etc., but for this re-evaluation it was decided to use half order of magnitude increments on a logarithmic scale of 0.03, 0.1, 0.3 etc. Changes were decided by the expert panel for 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (TEF=0.3), 1,2,3,7,8-pentachlorodibenzofuran (PeCDF) (TEF=0.03), octachlorodibenzo-p-dioxin (OCDD) and octachlorodibenzofuran (OCDF) (TEFs=0.0003), 3,4,4’,5-tetrachlorbiphenyl (PCB 81) (TEF=0.0003), 3,3’,4,4’,5,5’-hexachlorobiphenyl (PCB 169) (TEF=0.03) and a single TEF value (0.00003) for all relevant mono-ortho substituted PCBs. Additivity, an important prerequisite of the TEF concept was again confirmed by results from recent in vivo mixture studies. Some experimental evidence shows that nondioxin-like aryl hydrocarbon receptor (AhR) agonists/antagonists are able to impact the overall toxic potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds and this needs to be investigated further. Certain individual and groups of compounds were identified for possible future inclusion in the TEF concept, including 3,4,4’-TCB (PCB 37), polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs), mixed polyhalogenated dibenzo-p-dioxins and dibenzofurans, polyhalogenated naphthalenes and polybrominated biphenyls (PBBs). Concern was expressed about direct application of the TEF/TEQ approach to abiotic matrices such as soil, sediment etc., for direct application in human risk assessment. This is problematic, as the present TEF scheme and TEQ methodology is primarily intended for estimating exposure and risks via oral ingestion (e.g., by dietary intake). A number of future approaches to determine alternative or additional TEFs were also identified. These included the use of a probabilistic methodology to determine TEFs that better describe the associated levels of uncertainty and ‘systemic’ TEFs for blood and adipose tissue and total toxic equivalency (TEQ) for body burden. PMID:16829543
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Code of Federal Regulations, 2012 CFR
2012-04-01
... 21 Food and Drugs 7 2012-04-01 2012-04-01 false Potency tests, specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties. 660.54 Section 660.54 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR...
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Code of Federal Regulations, 2011 CFR
2011-04-01
... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Potency tests, specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties. 660.54 Section 660.54 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR...
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Code of Federal Regulations, 2013 CFR
2013-04-01
... 21 Food and Drugs 7 2013-04-01 2013-04-01 false Potency tests, specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties. 660.54 Section 660.54 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR...
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Code of Federal Regulations, 2014 CFR
2014-04-01
... 21 Food and Drugs 7 2014-04-01 2014-04-01 false Potency tests, specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties. 660.54 Section 660.54 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR...
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USDA-ARS?s Scientific Manuscript database
Botulinum neurotoxins (BoNTs) are one of the six highest-risk threat agents for bioterrorism, due to their extreme potency and lethality, ease of production, and need for prolonged intensive care of intoxicated patients. The current standard of treatment, equine antitoxin, has a high incidence of al...
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The mutagenic potency of ambient air PM in the Salmonella mutagenicity assay (rev/mg PM) varies only ~1 order of magnitude worldwide; however, the mutagenic potency of the air itself (rev/m3 of air) varies ~5 orders of magnitude (IARC Monograph Vol 109, 2016). Thus, the componen...
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Social Capital, Team Efficacy and Team Potency: The Mediating Role of Team Learning Behaviors
ERIC Educational Resources Information Center
van Emmerik, Hetty; Jawahar, I. M.; Schreurs, Bert; de Cuyper, Nele
2011-01-01
Purpose: Drawing on social capital theory and self-identification theory, this study aims to examine the associations of two indicators of social capital, personal networks and deep-level similarity, with team capability measures of team efficacy and team potency. The central focus of the study is to be the hypothesized mediating role of team…
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Gorka, Alexander P.; Alumasa, John N.; Sherlach, Katy S.; Jacobs, Lauren M.; Nickley, Katherine B.; Brower, Jonathan P.; de Dios, Angel C.
2013-01-01
We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365–374, 2013). PMID:23114783
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Gorka, Alexander P; Alumasa, John N; Sherlach, Katy S; Jacobs, Lauren M; Nickley, Katherine B; Brower, Jonathan P; de Dios, Angel C; Roepe, Paul D
2013-01-01
We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365-374, 2013).
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DOE Office of Scientific and Technical Information (OSTI.GOV)
DeGoey, David A.; Grampovnik, David J.; Chen, Hui-Ju
2013-03-07
Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the P1 position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistantmore » mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.« less
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Potency trends of delta9-THC and other cannabinoids in confiscated marijuana from 1980-1997.
ElSohly, M A; Ross, S A; Mehmedic, Z; Arafat, R; Yi, B; Banahan, B F
2000-01-01
The analysis of 35,312 cannabis preparations confiscated in the USA over a period of 18 years for delta-9-tetrahydrocannabinol (delta9-THC) and other major cannabinoids is reported. Samples were identified as cannabis, hashish, or hash oil. Cannabis samples were further subdivided into marijuana (loose material, kilobricks and buds), sinsemilla, Thai sticks and ditchweed. The data showed that more than 82% of all confiscated samples were in the marijuana category for every year except 1980 (61%) and 1981 (75%). The potency (concentration of delta9-THC) of marijuana samples rose from less than 1.5% in 1980 to approximately 3.3% in 1983 and 1984, then fluctuated around 3% till 1992. Since 1992, the potency of confiscated marijuana samples has continuously risen, going from 3.1% in 1992 to 4.2% in 1997. The average concentration of delta9-THC in all cannabis samples showed a gradual rise from 3% in 1991 to 4.47% in 1997. Hashish and hash oil, on the other hand, showed no specific potency trends. Other major cannabinoids [cannabidiol (CBD), cannabinol (CBN), and cannabichromene (CBC)] showed no significant change in their concentration over the years.
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Potential application of the consistency approach for vaccine potency testing.
Arciniega, J; Sirota, L A
2012-01-01
The Consistency Approach offers the possibility of reducing the number of animals used for a potency test. However, it is critical to assess the effect that such reduction may have on assay performance. Consistency of production, sometimes referred to as consistency of manufacture or manufacturing, is an old concept implicit in regulation, which aims to ensure the uninterrupted release of safe and effective products. Consistency of manufacture can be described in terms of process capability, or the ability of a process to produce output within specification limits. For example, the standard method for potency testing of inactivated rabies vaccines is a multiple-dilution vaccination challenge test in mice that gives a quantitative, although highly variable estimate. On the other hand, a single-dilution test that does not give a quantitative estimate, but rather shows if the vaccine meets the specification has been proposed. This simplified test can lead to a considerable reduction in the number of animals used. However, traditional indices of process capability assume that the output population (potency values) is normally distributed, which clearly is not the case for the simplified approach. Appropriate computation of capability indices for the latter case will require special statistical considerations.
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Factors Affecting the Inclusion Potency for Acicular Ferrite Nucleation in High-Strength Steel Welds
NASA Astrophysics Data System (ADS)
Kang, Yongjoon; Jeong, Seonghoon; Kang, Joo-Hee; Lee, Changhee
2016-06-01
Factors affecting the inclusion potency for acicular ferrite nucleation in high-strength weld metals were investigated and the contribution of each factor was qualitatively evaluated. Two kinds of weld metals with different hardenabilities were prepared, in both, MnTi2O4-rich spinel formed as the predominant inclusion phase. To evaluate the factors determining the inclusion potency, the inclusion characteristics of size, phase distribution in the multiphase inclusion, orientation relationship with ferrite, and Mn distribution near the inclusion were analyzed. Three factors affecting the ferrite nucleation potency of inclusions were evaluated: the Baker-Nutting (B-N) orientation relationship between ferrite and the inclusion; the formation of an Mn-depleted zone (MDZ) near the inclusion; and the strain energy around the inclusion. Among these, the first two factors were found to be the most important. In addition, it was concluded that the increased chemical driving force brought about by the formation of an MDZ contributed more to the formation of acicular ferrite in higher-strength weld metals, because the B-N orientation relationship between ferrite and the inclusion was less likely to form as the transformation temperature decreased.
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The International Standard for Oxytetracycline
Humphrey, J. H.; Lightbown, J. W.; Mussett, M. V.; Perry, W. L. M.
1955-01-01
The first attempt to set up an international standard for oxytetracycline, using oxytetracycline hydrochloride, failed because of difficulties in obtaining a preparation whose moisture content was uniform after distribution into ampoules. A preparation of dihydrate of oxytetracycline base was obtained instead, and was compared in an international collaborative assay with a sample of oxytetracycline hydrochloride, which was the current working standard of Chas. Pfizer & Co., Inc., USA. The results of the collaborative assay showed that the potency of the dihydrate was uniform, and that it was a suitable preparation for use as the International Standard. Evidence was obtained, however, that the reference preparation at the time of examination was less potent than had been originally supposed, and that it was hydrated. The potency of the proposed international standard was recalculated after allowance for water in the reference preparation, and the resulting biological potency agreed well with that to be expected on the basis of the physicochemical properties of the preparation. It was agreed, therefore, that the recalculated values should be used, and the preparation of oxytetracycline base dihydrate used in the collaborative assay is established as the International Standard for Oxytetracycline with a potency of 900 International Units per mg. PMID:13284563
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Characteristics of recombinantly expressed rat and human histamine H3 receptors.
Wulff, Birgitte S; Hastrup, Sven; Rimvall, Karin
2002-10-18
Human and rat histamine H(3) receptors were recombinantly expressed and characterized using receptor binding and a functional cAMP assay. Seven of nine agonists had similar affinities and potencies at the rat and human histamine H(3) receptor. S-alpha-methylhistamine had a significantly higher affinity and potency at the human than rat receptor, and for 4-[(1R*,2R*)-2-(5,5-dimethyl-1-hexynyl)cyclopropyl]-1H-imidazole (Perceptin) the preference was the reverse. Only two of six antagonists had similar affinities and potencies at the human and the rat histamine H(3) receptor. Ciproxifan, thioperamide and (1R*,2R*)-trans-2-imidazol-4 ylcyclopropyl) (cyclohexylmethoxy) carboxamide (GT2394) had significantly higher affinities and potencies at the rat than at the human histamine H(3) receptor, while for N-(4-chlorobenzyl)-N-(7-pyrrolodin-1-ylheptyl)guanidine (JB98064) the preference was the reverse. All antagonists also showed potent inverse agonism properties. Iodoproxyfan, Perceptin, proxyfan and GR175737, compounds previously described as histamine H(3) receptor antagonists, acted as full or partial agonists at both the rat and the human histamine H(3) receptor. Copyright 2002 Elsevier Science B.V.
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NASA Astrophysics Data System (ADS)
Mahata, C. R.
2012-12-01
Response of living bodies to different vastly `diluted' homeopathic medicines are different (rejecting the sceptic's view of `placebo' effect), though they are chemically same. Till now there is no satisfactory answer to how one such medicine differs from another in terms of scientifically measurable parameters. This paper tries to address this basic issue by taking two medicines of the same potency and two different potencies of the same medicine, namely, Arnica Mont 30c, 200c and Anacardium Orient 30c, 200c. These potencies are well above the Avogadro limit. The investigation reported here proceeds with the concept of `induced molecular structure' advanced by a number of scientists. Dielectric dispersion is used as the tool for experimental verification. It is based on the fact that when the exciting frequency of applied electric field equals the characteristic frequency, then macromolecules resonate leading to anomalous dielectric dispersion associated with sharp increase in dielectric loss, the resonance frequencies being different for macromolecules of different structures or dimensions. The results suggest that medicine- and potency-specific attributes are acquired by the vehicle (i.e. water) in the form of macromolecules generated by the potentization process of homeopathy making one medicine structurally different from another.
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Murray, Robin M.; Quigley, Harriet; Quattrone, Diego; Englund, Amir; Di Forti, Marta
2016-01-01
Epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychotic outcomes, and confirms a dose‐response relationship between the level of use and the risk of later psychosis. High‐potency cannabis and synthetic cannabinoids carry the greatest risk. Experimental administration of tetrahydrocannabinol, the active ingredient of cannabis, induces transient psychosis in normal subjects, but this effect can be ameliorated by co‐administration of cannabidiol. This latter is a constituent of traditional hashish, but is largely absent from modern high‐potency forms of cannabis. Argument continues over the extent to which genetic predisposition is correlated to, or interacts with, cannabis use, and what proportion of psychosis could be prevented by minimizing heavy use. As yet, there is not convincing evidence that cannabis use increases risk of other psychiatric disorders, but there are no such doubts concerning its detrimental effect on cognitive function. All of the negative aspects are magnified if use starts in early adolescence. Irrespective of whether use of cannabis is decriminalized or legalized, the evidence that it is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high‐potency cannabis and synthetic cannabinoids. PMID:27717258
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Dastmalchi, S; Barzegar-Jalali, M
2000-07-20
The most important group of nonspecific drugs is that of the general anesthetics. These nonspecific compounds vary greatly in structure, from noble gases such as Ar or Xe to complex steroids. Since the development of clinical anesthesia over a century ago, there has been a vast amount of research and speculation concerning the mechanism of action of general anesthetics. Despite these efforts, the exact mechanism remains unknown. Many theories of narcosis do not explain how unconsciousness is produced at a molecular level, but instead relate some physicochemical property of anesthetic agents to their anesthetic potencies. In this paper, we address some of those physicochemical properties, with more emphasis on correlating the anesthetic potency of volatile anesthetics to their boiling points based on thermodynamic principles.
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Synthetic risks, risk potency, and carcinogen regulation.
Viscusi, W K; Hakes, J K
1998-01-01
This article analyzes a comprehensive sample of over 350 chemicals tested for carcinogenicity to assess the determinants of the probability of regulation. Controlling for differences in the risk potency and noncancer risks, synthetic chemicals have a significantly higher probability of regulation overall: this is due to the greater likelihood of U.S. Food and Drug Administration (FDA) regulation. Measures of risk potency increase the probability of regulation by the U.S. Environmental Protection Agency (EPA), have a somewhat weaker positive effect on regulation by the U.S. Occupational Safety and Health Administration (OSHA), and decrease the likelihood of regulation by the FDA. The overall regulatory pattern is one in which the FDA targets synthetic chemicals and chemicals that pose relatively minor cancer risk. The EPA particularly performed more sensibly than many critics have suggested.
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NASA Astrophysics Data System (ADS)
Rahmi, Miftahul; Qiram, Ikhwanul
2018-05-01
Banyuwangi district has some Japanese caves and bunkers of World War II. The location of the objects are along the Banyuwangi coast as a maritime defense during the war. This structures can be used as education historical tourism object. There are many similar structures in other area that have been neglected and do not get enough preservation attention. This research is aimed to identify the potency of education historical tourism of Japanese caves and bunker in Banyuwangi. The research is done by field research for the observation of objects physical condition. It is also done by interviewing local government, historical actors and surrounding community. The result shows that the caves and bunker have a great potency but have not been used as education historical object.
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Yang, Bin; Hird, Alexander W; Russell, Daniel John; Fauber, Benjamin P; Dakin, Les A; Zheng, Xiaolan; Su, Qibin; Godin, Robert; Brassil, Patrick; Devereaux, Erik; Janetka, James W
2012-07-15
Cell-based subset screening of compounds using a Gli transcription factor reporter cell assay and shh stimulated cell differentiation assay identified a series of bisamide compounds as hedgehog pathway inhibitors with good potency. Using a ligand-based optimization strategy, heteroaryl groups were utilized as conformationally restricted amide isosteres replacing one of the amides which significantly increased their potency against SMO and the hedgehog pathway while decreasing activity against p38α kinase. We report herein the identification of advanced lead compounds such as imidazole 11c and 11f encompassing good p38α selectivity, low nanomolar potency in both cell assays, excellent physiochemical properties and in vivo pharmacokinetics. Copyright © 2012 Elsevier Ltd. All rights reserved.
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NASA Astrophysics Data System (ADS)
Pooler, John P.
1988-02-01
Several xanthene sensitizers were compared as sensitizers of membrane function in erythrocytes and some of their physico-chemical properties were examined. Eosin derivatives that localize at different membrane sites were equally effective at sensitizing both ion leaks and inactivation of membrane cholinesterase, implying that a diffusible intermediate reacts with membrane targets. Assessments of membrane loading and calculations of diffusion distances for singlet oxygen indicate that amounts of membrane-located sensitizer are quantitatively much greater than amounts in the nearby reaction medium. Potency measurements and assessment of absorption spectra and singlet oxygen production in water-dioxane mixtures lead to the conclusion that differential sorption to membranes, photon capture in low polarity environments and conversion of excited states to singlet oxygen are they key determinants of sensitizing potency.
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The stability of human, bovine and avian tuberculin purified protein derivative (PPD).
Maes, Mailis; Giménez, José Francisco; D'Alessandro, Adriana; De Waard, Jacobus H
2011-11-15
Guidelines recommend storing tuberculin purified protein derivative (PPD) refrigerated. However, especially in developing countries, maintaining the product refrigerated under field conditions can be difficult, limiting its use. Here we determine the effect of prolonged exposure to high temperatures on the potency of human, bovine and avian tuberculin PPD. Human, bovine and avian tuberculin PPD were stored for several weeks exposed to temperatures ranging from 37º to 100ºC. The potency was evaluated in vivo, in sensitized or naturally infected animals. Most test situations didn't affect the biological activity of the tuberculin PPDs and only very long and extreme incubations (several days at 100 °C) compromised the potency. Tuberculin PPD is very stable and can be stored or transported for long periods without refrigeration.
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Schwanstecher, C; Meyer, M; Schwanstecher, M; Panten, U
1998-03-01
1. The structure activity relationships for the insulin secretagogues N-benzoyl-D-phenylalanine (NBDP) and related compounds were examined at the sulphonylurea receptor level by use of cultured HIT-T15 and mouse pancreatic beta-cells. The affinities of these compounds for the sulphonylurea receptor were compared with their potencies for K(ATP)-channel inhibition. In addition, the effects of cytosolic nucleotides on K(ATP)-channel inhibition by NBDP were investigated. 2. NBDP displayed a dissociation constant for binding to the sulphonylurea receptor (K(D) value) of 11 microM and half-maximally effective concentrations of K(ATP)-channel inhibition (EC50 values) between 2 and 4 microM (in the absence of cytosolic nucleotides or presence of 0.1 mM GDP or 1 mM ADP). 3. In the absence of cytosolic nucleotides or presence of GDP (0.1 mM) maximally effective concentrations of NBDP (0.1-1 mM) reduced K(ATP)-channel activity to 47% and 44% of control, respectively. In the presence of ADP (1 mM), K(ATP)-channel activity was completely suppressed by 0.1 mM NBDP. 4. The L-isomer of N-benzoyl-phenylalanine displayed a 20 fold lower affinity and an 80 fold lower potency than the D-isomer. 5. Introduction of a p-nitro substituent in the D-phenylalanine moiety of NBDP did not decrease lipophilicity but lowered affinity and potency by more than 30 fold. 6. Introduction of a p-amino substituent in the D-phenylalanine moiety of NBDP (N-benzoyl-p-amino-D-phenylalanine, NBADP) reduced lipophilicity and lowered affinity and potency by about 10 fold. This loss of affinity and potency was compensated for by formation of the phenylpropionic acid derivative of NBADP. A similar difference in affinity was observed for the sulphonylurea carbutamide and its phenylpropionic acid derivative. 7. Replacing the benzene ring in the D-phenylalanine moiety of NBDP by a cyclohexyl ring increased lipophilicity, and the K(D) and EC50 values were slightly lower than for NBDP. Exchange of both benzene rings in NBDP by cyclohexyl rings further increased lipophilicity without altering affinity and potency. 8. This study shows that N-acylphenylalanines interact with the sulphonylurea receptor of pancreatic beta-cells in a stereospecific manner. Their potency depends on lipophilic but not aromatic properties of their benzene rings. As observed for sulphonylureas, interaction of N-acylphenylalanines with the sulphonylurea receptor does not induce complete inhibition of K(ATP)-channel activity in the absence of inhibitory cytosolic nucleotides.
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Schwanstecher, Christina; Meyer, Miriam; Schwanstecher, Mathias; Panten, Uwe
1998-01-01
The structure activity relationships for the insulin secretagogues N-benzoyl-D-phenylalanine (NBDP) and related compounds were examined at the sulphonylurea receptor level by use of cultured HIT-T15 and mouse pancreatic β-cells. The affinities of these compounds for the sulphonylurea receptor were compared with their potencies for KATP-channel inhibition. In addition, the effects of cytosolic nucleotides on KATP-channel inhibition by NBDP were investigated.NBDP displayed a dissociation constant for binding to the sulphonylurea receptor (KD value) of 11 μM and half-maximally effective concentrations of KATP-channel inhibition (EC50 values) between 2 and 4 μM (in the absence of cytosolic nucleotides or presence of 0.1 mM GDP or 1 mM ADP).In the absence of cytosolic nucleotides or presence of GDP (0.1 mM) maximally effective concentrations of NBDP (0.1–1 mM) reduced KATP-channel activity to 47% and 44% of control, respectively. In the presence of ADP (1 mM), KATP-channel activity was completely suppressed by 0.1 mM NBDP.The L-isomer of N-benzoyl-phenylalanine displayed a 20 fold lower affinity and an 80 fold lower potency than the D-isomer.Introduction of a p-nitro substituent in the D-phenylalanine moiety of NBDP did not decrease lipophilicity but lowered affinity and potency by more than 30 fold.Introduction of a p-amino substituent in the D-phenylalanine moiety of NBDP (N-benzoyl-p-amino-D-phenylalanine, NBADP) reduced lipophilicity and lowered affinity and potency by about 10 fold. This loss of affinity and potency was compensated for by formation of the phenylpropionic acid derivative of NBADP. A similar difference in affinity was observed for the sulphonylurea carbutamide and its phenylpropionic acid derivative.Replacing the benzene ring in the D-phenylalanine moiety of NBDP by a cyclohexyl ring increased lipophilicity, and the KD and EC50 values were slightly lower than for NBDP. Exchange of both benzene rings in NBDP by cyclohexyl rings further increased lipophilicity without altering affinity and potency.This study shows that N-acylphenylalanines interact with the sulphonylurea receptor of pancreatic β-cells in a stereospecific manner. Their potency depends on lipophilic but not aromatic properties of their benzene rings. As observed for sulphonylureas, interaction of N-acylphenylalanines with the sulphonylurea receptor does not induce complete inhibition of KATP-channel activity in the absence of inhibitory cytosolic nucleotides. PMID:9559882
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A review on the ethnomedicinal uses, phytochemistry and pharmacology of Alpinia officinarum Hance.
Abubakar, Ibrahim Babangida; Malami, Ibrahim; Yahaya, Yakubu; Sule, Sahabi Manga
2018-05-25
Alpinia officinarum Hance is a perennial plant that has been traditionally used for many decades to treat several ailments including inflammation, pain, stomach-ache, cold, amongst others. Pharmacological studies over the years have demonstrated remarkable bioactivities that could be further explored for development of new therapeutic agents against various ailments. The paper critically reviewed the ethno-medicinal uses, pharmacology, and phytochemistry of A. officinarum. Keywords including A. officinarum and its synonyms were searched using electronic databases including ISI web of knowledge, Science direct, Scopus, PubMed, Google scholar and relevant database for Masters and Doctoral theses. A. officinarum is prepared in Asia, Turkey, Morocco and Iran as a decoction, infusion or juice as a single preparation or in combination with other herbs, food or drinks for the treatment of general health problems including cold, inflammation, digestive disorders, etc. Pharmacological studies revealed the potent in vitro and in vivo bioactivities of various parts of A. officinarum that include anti-inflammatory, cytotoxicity, homeostasis, lipid regulation, antioxidant, antiviral, antimicrobial, antiosteoporosis, etc. Over 90 phytochemical constituents have been identified and isolated from A. officinarum comprising vastly of phenolic compounds especially diarylheptanoids isolated from the rhizome and considered the most active bioactive components. In vitro and in vivo studies have confirmed the potency of A. officinarum. However, further studies are required to establish the mechanisms mediating its bioactivities in relation to the medicinal uses as well as investigating any potential toxicity for future clinical studies. Copyright © 2018 Elsevier B.V. All rights reserved.
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van den Berg, Martin
2013-01-01
In 2011, a joint World Health Organization (WHO) and United Nations Environment Programme (UNEP) expert consultation took place, during which the possible inclusion of brominated analogues of the dioxin-like compounds in the WHO Toxicity Equivalency Factor (TEF) scheme was evaluated. The expert panel concluded that polybrominated dibenzo-p-dioxins (PBDDs), dibenzofurans (PBDFs), and some dioxin-like biphenyls (dl-PBBs) may contribute significantly in daily human background exposure to the total dioxin toxic equivalencies (TEQs). These compounds are also commonly found in the aquatic environment. Available data for fish toxicity were evaluated for possible inclusion in the WHO-UNEP TEF scheme (van den Berg et al., 1998). Because of the limited database, it was decided not to derive specific WHO-UNEP TEFs for fish, but for ecotoxicological risk assessment, the use of specific relative effect potencies (REPs) from fish embryo assays is recommended. Based on the limited mammalian REP database for these brominated compounds, it was concluded that sufficient differentiation from the present TEF values of the chlorinated analogues (van den Berg et al., 2006) was not possible. However, the REPs for PBDDs, PBDFs, and non-ortho dl-PBBs in mammals closely follow those of the chlorinated analogues, at least within one order of magnitude. Therefore, the use of similar interim TEF values for brominated and chlorinated congeners for human risk assessment is recommended, pending more detailed information in the future. PMID:23492812
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van den Berg, Martin; Denison, Michael S; Birnbaum, Linda S; Devito, Michael J; Fiedler, Heidelore; Falandysz, Jerzy; Rose, Martin; Schrenk, Dieter; Safe, Stephen; Tohyama, Chiharu; Tritscher, Angelika; Tysklind, Mats; Peterson, Richard E
2013-06-01
In 2011, a joint World Health Organization (WHO) and United Nations Environment Programme (UNEP) expert consultation took place, during which the possible inclusion of brominated analogues of the dioxin-like compounds in the WHO Toxicity Equivalency Factor (TEF) scheme was evaluated. The expert panel concluded that polybrominated dibenzo-p-dioxins (PBDDs), dibenzofurans (PBDFs), and some dioxin-like biphenyls (dl-PBBs) may contribute significantly in daily human background exposure to the total dioxin toxic equivalencies (TEQs). These compounds are also commonly found in the aquatic environment. Available data for fish toxicity were evaluated for possible inclusion in the WHO-UNEP TEF scheme (van den Berg et al., 1998). Because of the limited database, it was decided not to derive specific WHO-UNEP TEFs for fish, but for ecotoxicological risk assessment, the use of specific relative effect potencies (REPs) from fish embryo assays is recommended. Based on the limited mammalian REP database for these brominated compounds, it was concluded that sufficient differentiation from the present TEF values of the chlorinated analogues (van den Berg et al., 2006) was not possible. However, the REPs for PBDDs, PBDFs, and non-ortho dl-PBBs in mammals closely follow those of the chlorinated analogues, at least within one order of magnitude. Therefore, the use of similar interim TEF values for brominated and chlorinated congeners for human risk assessment is recommended, pending more detailed information in the future.
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NASA Astrophysics Data System (ADS)
Karmakar, Shyamal; Ghergut, Julia; Sauter, Martin
2015-04-01
Artificial-fracture design, and fracture characterization during or following stimulation treatment is a central aspect of many EGS ('enhanced' or 'engineered' geothermal system) projects. During the creation or stimulation of an EGS, the injection of fluids, followed by flowback and production stages offers the opportunity for conducting various tracer tests in a single-well (SW) configuration, and given the typical operational and time limitations associated with such tests, along with the need to assess treatment success in real time, investigators mostly favour using short-time tracer-test data, rather than awaiting long-term 'tailings' of tracer signals. Late-time tracer signals from SW injection-flowback and production tests have mainly been used for the purpose of multiple-fracture inflow profiling in multi-layer reservoirs [1]. However, the potential of using SW short-term tracer signals for fracture characterization [2, 3] remained little explored as yet. Dealing with short-term flowback signals, we face a certain degree of parameter interplay, leading to ambiguity in fracture parameter inversion from the measured signal of a single tracer. This ambiguity can, to a certain extent, be overcome by - combining different sources of information (lithostratigraphy, and hydraulic monitoring) in order to constrain the variation range of hydrogeologic parameters (matrix and fracture permeability and porosity, fracture size), - using different types of tracers, such as conservative tracer pairs with contrasting diffusivity, or tracers pairs with contrasting sorptivity onto target surfaces. Fracture height is likely to be constrained by lithostratigraphy, while fracture length is supposed to be determinable from hydraulic monitoring (pressure recordings); the flowback rate can be assumed as a known (measurable) quantity during individual-fracture flowback. This leaves us with one or two unknown parameters to be determined from tracer signals: - the transport-effective aperture, in a water fracture (WF), or - fracture thickness and porosity, for a gel-proppant fracture (GPF). We find that parameter determination from SW early signals can significantly be improved by concomitantly using a number of solute tracers with different transport and retardation behaviour. We considered tracers of different sorptivity to proppant coatings, and to matrix rock surfaces, for GPF, as well as contrasting-diffusivity or -sorptivity tracers, for WF. An advantage of this SW approach is that it requires only small chaser volumes (few times the fracture volume), not relying on advective penetration into the rock matrix. Thus, selected tracer species are to be injected during the very last stage of the fracturing process, when fracture sizes and thus target parameters are supposed to attain more or less stable values. We illustrate the application of these tracer test design principles using hydro- and lithostratigraphy data from the Geothermal Research Platform at Groß Schönebeck [4], targeting a multi-layer reservoir (sedimentary and crystalline formations in 4-5 km depth) in the NE-German Sedimentary Basin. Acknowledgments: This work benefited from long-term support from Baker Hughes (Celle) and from the Lower-Saxonian Science and Culture Ministry (MWK Niedersachsen) within the applied research project gebo (Geothermal Energy and High-Performance Drilling, 2009-2014). The first author gratefully acknowledges continued financial support from the DAAD (German Academic Exchange Service) to pursuing Ph. D. work. References: [1] http://www.sciencedirect.com/science/article/pii/S1876610214017391 [2] http://www.geothermal-energy.org/cpdb/record_detail.php?id=7215 [3] http://www.geothermal-energy.org/cpdb/record_detail.php?id=19034 [4] http://www.gfz-potsdam.de/en/scientific-services/laboratories/gross-schoenebeck/
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Guidance on Nanomaterial Hazards and Risks
2015-05-21
and at room temperature and 37 C°– solid separation by centrifugation, filtration , or chemical techniques (more experimental techniques combining...members in this potency sequence using bolus in vivo testing, verify the bolus results with selective inhalation testing. The potency of members of...measures in in vitro and limited in vivo experimental systems would facilitate the characterization of dose-response relationships across a set of ENMs
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ERIC Educational Resources Information Center
Chu, Regina Juchun; Chu, Anita Zichun
2010-01-01
The present study intends to explore the role of collectivism and group potency at group level in predicting individual Internet self-efficacy (ISE) and individual e-learning outcomes for people aged over 45. Group learning has been widely discussed in the research into online formats. However, less study has been carried out about how…
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2014-01-01
Background Due to the recent European legislations posing a ban of animal tests for safety assessment within the cosmetic industry, development of in vitro alternatives for assessment of skin sensitization is highly prioritized. To date, proposed in vitro assays are mainly based on single biomarkers, which so far have not been able to classify and stratify chemicals into subgroups, related to risk or potency. Methods Recently, we presented the Genomic Allergen Rapid Detection (GARD) assay for assessment of chemical sensitizers. In this paper, we show how the genome wide readout of GARD can be expanded and used to identify differentially regulated pathways relating to individual chemical sensitizers. In this study, we investigated the mechanisms of action of a range of skin sensitizers through pathway identification, pathway classification and transcription factor analysis and related this to the reactive mechanisms and potency of the sensitizing agents. Results By transcriptional profiling of chemically stimulated MUTZ-3 cells, 33 canonical pathways intimately involved in sensitization to chemical substances were identified. The results showed that metabolic processes, cell cycling and oxidative stress responses are the key events activated during skin sensitization, and that these functions are engaged differently depending on the reactivity mechanisms of the sensitizing agent. Furthermore, the results indicate that the chemical reactivity groups seem to gradually engage more pathways and more molecules in each pathway with increasing sensitizing potency of the chemical used for stimulation. Also, a switch in gene regulation from up to down regulation, with increasing potency, was seen both in genes involved in metabolic functions and cell cycling. These observed pathway patterns were clearly reflected in the regulatory elements identified to drive these processes, where 33 regulatory elements have been proposed for further analysis. Conclusions This study demonstrates that functional analysis of biomarkers identified from our genomics study of human MUTZ-3 cells can be used to assess sensitizing potency of chemicals in vitro, by the identification of key cellular events, such as metabolic and cell cycling pathways. PMID:24517095
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Wolfrum, Katherine M.; Reed, John F.; Kim, Sunyoung O.; Swanson, Tracy; Johnson, Robert A.; Janowsky, Aaron
2017-01-01
Synthetic cathinones are components of “bath salts” and have physical and psychologic side effects, including hypertension, paranoia, and hallucinations. Here, we report interactions of 20 “bath salt” components with human dopamine, serotonin, and norepinephrine transporters [human dopamine transporter (hDAT), human serotonin transporter (hSERT), and human norepinephrine transporter (hNET), respectively] heterologously expressed in human embryonic kidney 293 cells. Transporter inhibitors had nanomolar to micromolar affinities (Ki values) at radioligand binding sites, with relative affinities of hDAT>hNET>hSERT for α-pyrrolidinopropiophenone (α-PPP), α-pyrrolidinobutiophenone, α-pyrrolidinohexiophenone, 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone, 3,4-methylenedioxy-α-pyrrolidinopropiophenone, 3,4-methylenedioxy-α-pyrrolidinobutiophenone, 4-methyl-α-pyrrolidinopropiophenone, α-pyrrolidinovalerophenone, 4-methoxy-α-pyrrolidinovalerophenone, α-pyrrolidinopentiothiophenone (alpha-PVT), and α-methylaminovalerophenone, and hDAT>hSERT>hNET for methylenedioxypentedrone. Increasing the α-carbon chain length increased the affinity and potency of the α-pyrrolidinophenones. Uptake inhibitors had relative potencies of hDAT>hNET>hSERT except α-PPP and α-PVT, which had highest potencies at hNET. They did not induce [3H]neurotransmitter release. Substrates can enter presynaptic neurons via transporters, and the substrates methamphetamine and 3,4-methylenedioxymethylamphetamine are neurotoxic. We determined that 3-fluoro-, 4-bromo-, 4-chloro-methcathinone, and 4-fluoroamphetamine were substrates at all three transporters; 5,6-methylenedioxy-2-aminoindane (MDAI) and 4-methylethcathinone (4-MEC) were substrates primarily at hSERT and hNET; and 3,4-methylenedioxy-N-ethylcathinone (ethylone) and 5-methoxy-methylone were substrates only at hSERT and induced [3H]neurotransmitter release. Significant correlations between potencies for inhibition of uptake and for inducing release were observed for these and additional substrates. The excellent correlation of efficacy at stimulating release versus Ki/IC50 ratios suggested thresholds of binding/uptake ratios above which compounds were likely to be substrates. Based on their potencies at hDAT, most of these compounds have potential for abuse and addiction. 4-Bromomethcathinone, 4-MEC, 5-methoxy-methylone, ethylone, and MDAI, which have higher potencies at hSERT than hDAT, may have empathogen psychoactivity. PMID:27799294
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Lipworth, B. J.; Newnham, D. M.; Clark, R. A.; Dhillon, D. P.; Winter, J. H.; McDevitt, D. G.
1995-01-01
BACKGROUND--There is controversy as to the relative safety of fenoterol and salbutamol. No differences have been found in the relative cardiac beta 1/beta 2 receptor activity of inhaled fenoterol and salbutamol in normal subjects. These initial findings have been extended by comparing the respective potencies of equivalent doses by weight of fenoterol and salbutamol in asthmatic subjects, in terms of airways and systemic responses. METHODS--Eighteen asthmatic patients of mean (SD) age 40 (14) years and a forced expiratory volume in one second (FEV1)% predicted of 56 (14)% (1.97 (0.66)1) were randomised to inhale fenoterol (100 micrograms/puff or 200 micrograms/puff), salbutamol, or placebo (100 micrograms/puff or 200 micrograms/puff) on three separate days. Dose-response curves were constructed using cumulative doses of 100 micrograms, 200 micrograms, 400 micrograms, 1000 micrograms, 2000 micrograms, and 4000 micrograms, and airways and systemic responses were measured 20 minutes after each dose with 40 minute increments. Dose ratios for the relative potency of fenoterol versus salbutamol were calculated from the dose-response curves using regression analysis of parallel slopes. RESULTS--There was no difference in bronchodilator potency between fenoterol and salbutamol (as median dose ratio): FEV1 1.1 (95% CI 0.4 to 4.6). In contrast, dose ratios for systemic responses showed that fenoterol was more potent than salbutamol: serum potassium 3.7 (95% CI 2.0 to 6.0), tremor 5.7 (95% CI 1.4 to 10.2), heart rate 1.6 (95% CI 1.0 to 2.3). At a conventional dose of 200 micrograms the only difference in response between the two drugs was observed for tremor (as mean difference): 0.23 log units (95% CI 0.06 to 0.41 log units). CONCLUSIONS--There was no difference in the bronchodilator potency between fenoterol and salbutamol on a microgram equivalent basis. In contrast, systemic potency was greater with fenoterol, although this difference was not clinically relevant at conventional dosages up to 200 micrograms. PMID:7886650
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Loa, Jacky; Chow, Pierce; Zhang, Kai
2009-05-01
To study anticancer activities of 68 plant polyphenols with different backbone structures and various substitutions and to analyze the structure-activity relationships. Antiproliferative activity of 68 plant polyphenols on human liver cancer cells were screened by the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide method. Structure-activity relationships were analyzed by comparison of their activities with selected structures. Cell cycle progression was assayed by flow cytometry analysis and apoptosis was analyzed by DNA fragment assay. Based on their backbone structures, 68 polyphenols were sub-classed to flavonoids (chalcones, flavanones, flavones and isoflavones), chromones and coumarins. The order of their potency to suppress the human liver cancer cells is chalcones > flavones > chromones > isoflavones > flavanones > coumarins. Chalcones comprise the most potent group with IC(50) values ranging from 21.69 to 197 microM. Top nine most potent chalcones in the group have hydroxylation at 2'-carbon position in B-ring. Flavones ranked second in their potencies. Quercetin, 4-hydroxyflavone and luteolin are three hydroxyflavones with highest potencies in this group. Their IC(50) values are 30.81, 39.29 and 71.17 microM, respectively. Chromones, isoflavones, flavanones and coumarins showed much lower potencies when compared to the first two groups with IC(50) ranges of 61 to >400, 131 to >400, 138 to >400 and 360.85 to >400 microM, respectively. In mechanistic studies, the most potent chalcone, 2,2'-dihydroxychalcone could induce G2/M arrest and then apoptosis of the cancer cells. An analysis of structure-activity relationship showed that following structures are required for their inhibitory potencies on human liver cancer cells: (1) of the six sub-classes of the polyphenols tested, the unique backbone structure of chalcones with a open C-ring; (2) within the chalcone group, hydroxyl substitution at 2'-carbon of B-ring; (3) hydroxyl substitution at 3'-carbon in B-ring of flavones. However, some other structures were found to decrease their potencies: e.g. substitutions by sugar moieties in flavones. These data are valuable for design and modification of new polyphenols, which could be potential antiproliferative agents of cancer cells.
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Qi, Tao; Ly, Kien; Poyner, David R; Christopoulos, George; Sexton, Patrick M; Hay, Debbie L
2011-05-01
The receptors for calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are complexes of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMP). The CGRP receptor is a CLR/RAMP1 pairing whereas CLR/RAMP2 and CLR/RAMP3 constitute two subtypes of AM receptor: AM(1) and AM(2), respectively. Previous studies identified Glu74 in RAMP3 to be important for AM binding and potency. To further understand the importance of this residue and its equivalent in RAMP1 (Trp74) we substituted the native amino acids with several others. In RAMP3, these were Trp, Phe, Tyr, Ala, Ser, Thr, Arg and Asn; in RAMP1, Glu, Phe, Tyr, Ala and Asn substitutions were made. The mutant RAMPs were co-expressed with CLR in Cos7 cells; receptor function in response to AM, AM(2)/intermedin and CGRP was measured in a cAMP assay and cell surface expression was determined by ELISA. Phe reduced AM potency in RAMP3 but had no effect in RAMP1. In contrast, Tyr had no effect in RAMP3 but enhanced AM potency in RAMP1. Most other substitutions had a small effect on AM potency in both receptors whereas there was little impact on CGRP or AM(2) potency. Overall, these data suggest that the geometry and charge of the residue at position 74 contribute to how AM interacts with the AM(2) and CGRP receptors and confirms the role of this position in dictating differential AM pharmacology at the AM(2) and CGRP receptors. Copyright © 2011. Published by Elsevier Inc.
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Colucci, Philippe; D'Angelo, Pina; Mautone, Giuseppe; Scarsi, Claudia; Ducharme, Murray P
2011-06-01
To assess the pharmacokinetic equivalence of a new soft capsule formulation of levothyroxine versus a marketed reference product and to assess the soft capsule formulated with stricter potency guidelines versus the capsule before the implementation of the new potency rule. Two single-dose randomized two-way crossover pharmacokinetic equivalence studies and one dosage form proportionality single-dose study comparing low, medium, and high strengths of the new formulation. All three studies were performed in a clinical setting. Participants were healthy male and female adult subjects with normal levothyroxine levels. A total of 90 subjects participated in the three studies. Pharmacokinetic parameters were calculated on baseline- adjusted concentrations. The first pharmacokinetic equivalence study compared the levothyroxine sodium soft capsule formulation (Tirosint) with the reference Synthroid tablets and the two products were considered bioequivalent. The dosage form proportionality study compared the 50-, 100-, and 150-μg test capsules strengths dosed at the same level (600 μg) and all three strengths were considered equivalent when given at the same dosage. The last study compared the test capsule used in the first two studies with a new capsule formulation following the new potency guideline (±5%) set forward by the Food and Drug Administration and the two capsules were considered bioequivalent. Doses were well tolerated by subjects in all three studies with no serious adverse events reported. The levothyroxine soft capsule formulated with the stricter new potency guideline set forward by the Food and Drug Administration met equivalence criteria in terms of rate and extent of exposure under fasting conditions to the reference tablet formulation. Clinical doses of the capsule formulation can be given using any combination of the commercialized strengths.
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Soeteman-Hernández, Lya G; Fellows, Mick D; Johnson, George E; Slob, Wout
2015-12-01
In this study, we explored the applicability of using in vitro micronucleus (MN) data from human lymphoblastoid TK6 cells to derive in vivo genotoxicity potency information. Nineteen chemicals covering a broad spectrum of genotoxic modes of action were tested in an in vitro MN test using TK6 cells using the same study protocol. Several of these chemicals were considered to need metabolic activation, and these were administered in the presence of S9. The Benchmark dose (BMD) approach was applied using the dose-response modeling program PROAST to estimate the genotoxic potency from the in vitro data. The resulting in vitro BMDs were compared with previously derived BMDs from in vivo MN and carcinogenicity studies. A proportional correlation was observed between the BMDs from the in vitro MN and the BMDs from the in vivo MN assays. Further, a clear correlation was found between the BMDs from in vitro MN and the associated BMDs for malignant tumors. Although these results are based on only 19 compounds, they show that genotoxicity potencies estimated from in vitro tests may result in useful information regarding in vivo genotoxic potency, as well as expected cancer potency. Extension of the number of compounds and further investigation of metabolic activation (S9) and of other toxicokinetic factors would be needed to validate our initial conclusions. However, this initial work suggests that this approach could be used for in vitro to in vivo extrapolations which would support the reduction of animals used in research (3Rs: replacement, reduction, and refinement). © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology.
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Domarkas, Juozas; Dudouit, Fabienne; Williams, Christopher; Qiyu, Qiu; Banerjee, Ranjita; Brahimi, Fouad; Jean-Claude, Bertrand Jacques
2006-06-15
According to the "combi-targeting" concept, the EGFR tyrosine kinase (TK) inhibitory potency of compounds termed "combi-molecules" is critical for selective growth inhibition of tumor cells with disordered expression of EGFR or its closest family member erbB2. Here we report on the optimization of the EGFR TK inhibitory potency of the combi-molecules of the nitrosourea class by comparison with their aminoquinazoline and ureidoquinazoline precursors. This led to the discovery of a new structural parameter that influences their EGFR TK inhibitory potency, i.e., the torsion angle between the plane of the quinazoline ring and the ureido or the nitrosoureido moiety of the synthesized drugs. Compounds (3'-Cl and Br series) with small angles (0.5-3 degrees ) were generally stronger EGFR TK inhibitors than those with large angles (18-21 degrees ). This was further corroborated by ligand-receptor van der Waals interaction calculations that showed significant binding hindrance imposed by large torsion angles in the narrow ATP cleft of EGFR. Selective antiproliferative studies in a pair of mouse fibroblast NIH3T3 cells, one of which NIH3T3/neu being transfected with the erbB2 oncogene, showed that IC(50) values for inhibition of EGFR TK could be good predictors of their selective potency against the serum-stimulated growth of the erbB2-tranfected cell line (Pearson r = 0.8). On the basis of stability (t(1/2)), EGFR TK inhibitory potency (IC(50)), and selective erbB2 targeting, compound 23, a stable nitrosourea, was considered to have the structural requirements for further development.
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Li, Na; Lu, Dongshi; Yang, Lei; Tao, Huan; Xu, Younian; Wang, Chenchen; Fu, Lisha; Liu, Hui; Chummum, Yatisha; Zhang, Shihai
2018-04-11
Xenon is an elemental anesthetic with nine stable isotopes. Nuclear spin is a quantum property which may differ among isotopes. Xenon 131 (Xe) has nuclear spin of 3/2, xenon 129 (Xe) a nuclear spin of 1/2, and the other seven isotopes have no nuclear spin. This study was aimed to explore the effect of nuclear spin on xenon anesthetic potency. Eighty C57BL/6 male mice (7 weeks old) were randomly divided into four groups, xenon 132 (Xe), xenon 134 (Xe), Xe, and Xe groups. Due to xenon's low potency, loss of righting reflex ED50 for mice to xenon was determined with 0.50% isoflurane. Loss of righting reflex ED50 of isoflurane was also measured, and the loss of righting reflex ED50 values of the four xenon isotopes were then calculated. The exact polarizabilities of the isotopes were calculated. Combined with 0.50% isoflurane, the loss of righting reflex ED50 values were 15 ± 4%, 16 ± 5%, 22 ± 5%, and 23 ± 7% for Xe, Xe, Xe, and Xe, respectively. For xenon alone, the loss of righting reflex ED50 values of Xe, Xe, Xe, and Xe were 70 ± 4%, 72 ± 5%, 99 ± 5%, and 105 ± 7%, respectively. Four isotopes had a same exact polarizability of 3.60 Å. Xenon isotopes with nuclear spin are less potent than those without, and polarizability cannot account for the difference. The lower anesthetic potency of Xe may be the result of it participating in conscious processing and therefore partially antagonizing its own anesthetic potency. Nuclear spin is a quantum property, and our results are consistent with theories that implicate quantum mechanisms in consciousness.
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Scott, Martin J.; Lee, Jennifer A.; Wake, Matthew S.; Batt, Kelly V.; Wattam, Trevor A.; Hiles, Ian D.; Batuwangala, Thil D.; Ashman, Claire I.; Steward, Michael
2017-01-01
ABSTRACT Bispecific antibodies (BsAbs) are emerging as an important class of biopharmaceutical. The majority of BsAbs are created from conventional antibodies or fragments engineered into more complex configurations. A recurring challenge in their development, however, is the identification of components that are optimised for inclusion in the final format in order to deliver both efficacy and robust biophysical properties. Using a modular BsAb format, the mAb-dAb, we assessed whether an ‘in-format’ screening approach, designed to select format-compatible domain antibodies, could expedite lead discovery. Human nerve growth factor (NGF) was selected as an antigen to validate the approach; domain antibody (dAb) libraries were screened, panels of binders identified, and binding affinities and potencies compared for selected dAbs and corresponding mAb-dAbs. A number of dAbs that exhibited high potency (IC50) when assessed in-format were identified. In contrast, the corresponding dAb monomers had ∼1000-fold lower potency than the formatted dAbs; such dAb monomers would therefore have been omitted from further characterization. Subsequent stoichiometric analyses of mAb-dAbs bound to NGF, or an additional target antigen (vascular endothelial growth factor), suggested different target binding modes; this indicates that the observed potency improvements cannot be attributed simply to an avidity effect offered by the mAb-dAb format. We conclude that, for certain antigens, screening naïve selection outputs directly in-format enables the identification of a subset of format-compatible dAbs, and that this offers substantial benefits in terms of molecular properties and development time. PMID:27786601
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Storm, J E; Rozman, K K
1998-06-01
The Occupational Safety and Health Administration (OSHA) methylene chloride Permissible Exposure Level (PEL) or 25 ppm is quantitatively derived from mouse tumor results observed in a high-exposure National Toxicology Program bioassay. Because this approach depends on controversial interspecies and low-dose extrapolations, the PEL itself has stimulated heated debate. Here, an alternative safety assessment for methylene chloride is presented. It is based on an acute human lowest-observed-adverse-effect level (LOAEL) of 200 ppm for subtle central nervous system (CNS) depression. Steep, parallel exposure-response curves for anesthetic and subanesthetic CNS effects associated with compounds mechanistically and structurally related to methylene chloride are shown to support a safety factor of two to account for inter-individual variability in response. LOAEL/no-observed-adverse-effect ratios for subtle CNS effects associated with structurally related solvents are shown to support a safety factor range of two to four to account for uncertainty in identifying a subthreshold exposure level. Anesthetic relative potencies and anesthetic/subanesthetic effect level ratios are shown to be constant for the compounds evaluated, demonstrating that subanesthetic relative potencies are also constant. Relative potencies among similarly derived occupational exposure limits (OELs) for solvents structurally related to methylene chloride are therefore used to validate the derived methylene chloride OEL range of 25-50 ppm. Because this safety assessment is based on human (rather than rodent) data and empirical (rather than theoretical) exposure-response relationships and is supported by relative potency analysis, it is a defensible alternative to to the OSHA risk assessment and should positively contribute to the debate regarding the appropriate basis and value for a methylene chloride PEL.
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Smith, Heidi L.; Cheslock, Peter; Leney, Mark; Barton, Bruce; Molrine, Deborah C.
2016-01-01
ABSTRACT Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving ≥ 27.5 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg S315/IU DAT (95% CI 16–21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 µg/IU (95% CI 38–59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans. PMID:27070129
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Critical elements in the development of cell therapy potency assays for ischemic conditions.
Porat, Yael; Abraham, Eytan; Karnieli, Ohad; Nahum, Sagi; Woda, Juliana; Zylberberg, Claudia
2015-07-01
A successful potency assay for a cell therapy product (CTP) used in the treatment of ischemic conditions should quantitatively measure relevant biological properties that predict therapeutic activity. This is especially challenging because of numerous degrees of complexity stemming from factors that include a multifactorial complex mechanism of action, cell source, inherent cell characteristics, culture method, administration mode and the in vivo conditions to which the cells are exposed. The expected biological function of a CTP encompasses complex interactions that range from a biochemical, metabolic or immunological activity to structural replacement of damaged tissue or organ. Therefore, the requirements for full characterization of the active substance with respect to biological function could be taxing. Moreover, the specific mechanism of action is often difficult to pinpoint to a specific molecular entity; rather, it is more dependent on the functionality of the cellular components acting in a in a multifactorial fashion. In the case of ischemic conditions, the cell therapy mechanism of action can vary from angiogenesis, vasculogenesis and arteriogenesis that may activate different pathways and clinical outcomes. The CTP cellular attributes with relation to the suggested mechanism of action can be used for the development of quantitative and reproducible analytical potency assays. CTPs selected and released on the basis of such potency assays should have the highest probability of providing meaningful clinical benefit for patients. This White Paper will discuss and give examples for key elements in the development of a potency assay for treatment of ischemic disorders treated by the use of CTPs. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
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Schuhmacher, S; Schulz, E; Oelze, M; König, A; Roegler, C; Lange, K; Sydow, L; Kawamoto, T; Wenzel, P; Münzel, T; Lehmann, J; Daiber, A
2009-01-01
Background and purpose: The chronic use of organic nitrates is limited by serious side effects including oxidative stress, nitrate tolerance and/or endothelial dysfunction. The side effects and potency of nitroglycerine depend on mitochondrial aldehyde dehydrogenase (ALDH-2). We sought to determine whether this concept can be extended to a new class of organic nitrates with amino moieties (aminoalkyl nitrates). Experimental approach: Vasodilator potency of the organic nitrates, in vitro tolerance and in vivo tolerance (after continuous infusion for 3 days) were assessed in wild-type and ALDH-2 knockout mice by isometric tension studies. Mitochondrial oxidative stress was analysed by L-012-dependent chemiluminescence and protein tyrosine nitration. Key results: Aminoethyl nitrate (AEN) showed an almost similar potency to glyceryl trinitrate (GTN), even though it is only a mononitrate. AEN-dependent vasodilatation was mediated by cGMP and nitric oxide. In contrast to triethanolamine trinitrate (TEAN) and GTN, AEN bioactivation did not depend on ALDH-2 and caused no in vitro tolerance. In vivo treatment with TEAN and GTN, but not with AEN, induced cross-tolerance to acetylcholine (ACh)-dependent and GTN-dependent relaxation. Although all nitrates tested induced tolerance to themselves, only TEAN and GTN significantly increased mitochondrial oxidative stress in vitro and in vivo. Conclusions and implications: The present results demonstrate that not all high potency nitrates are bioactivated by ALDH-2 and that high potency of a given nitrate is not necessarily associated with induction of oxidative stress or nitrate tolerance. Obviously, there are distinct pathways for bioactivation of organic nitrates, which for AEN may involve xanthine oxidoreductase rather than P450 enzymes. PMID:19563531
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Ginsburg, Brett C; Pinkston, Jonathan W; Lamb, Richard J
2012-04-01
The selective serotonin reuptake inhibitor fluvoxamine reduces responding for ethanol at lower doses than responding for food when each is available in separate components or separate groups of rats. However, when both are available concurrently and deliveries earned per session are equal, this apparent selectivity inverts and food-maintained behavior is more sensitive than ethanol-maintained behavior to rate-decreasing effects of fluvoxamine. Here, we investigated further the impact that concurrent access to both food and ethanol has on the potency of fluvoxamine. Fluvoxamine (5.6-17.8 mg/kg) potency was assessed under conditions in which food and ethanol were available concurrently and response rates were equal [average variable intervals (VIs) 405 and 14 s for food and ethanol, respectively], as well as when density of food delivery was increased (average VI 60 s for food and VI 14 s for ethanol). The potency of fluvoxamine was also determined when only ethanol was available (food extinction and average VI 14 s for ethanol) and under multiple VIs (VI 30 s for food and ethanol) wherein either food or ethanol was the only programmed reinforcement available during each component. Fluvoxamine was less potent at decreasing ethanol self-administration when food was available concurrently {ED50 [95% confidence limit (CL): 8.2 (6.5-10.3) and 10.7 (7.9-14.4)]} versus when ethanol was available in isolation [ED50: 4.0 (2.7-5.9) and 5.1 (4.3-6.0)]. Effects on food were similar under each condition in which food was available. The results demonstrate that the potency of fluvoxamine in reducing ethanol-maintained behavior depends on whether ethanol is available in isolation or in the context of concurrently scheduled food reinforcement.
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Silibinin derivatives as anti-prostate cancer agents: Synthesis and cell-based evaluations.
Vue, Bao; Zhang, Sheng; Zhang, Xiaojie; Parisis, Konstantinos; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong
2016-02-15
This study aims to systematically explore the alkylation effect of 7-OH in silibinin and 2,3-dehydrosilibinin on the antiproliferative potency toward three prostate cancer cell lines. Eight 7-O-alkylsilibinins, eight 7-O-alkyl-2,3-dehydrosilibinins, and eight 3,7-O-dialkyl-2,3-dehydrosilibinins have been synthesized from commercially available silibinin for the in vitro cell-based evaluation. The WST-1 cell proliferation assay indicates that nineteen out of twenty-four silibinin derivatives have significantly improved antiproliferative potency when compared with silibinin. 7-O-Methylsilibinin (2) and 7-O-ethylsilibinin (3) have been identified as the most potent compounds with 98- and 123-fold enhanced potency against LNCaP human androgen-dependent prostate cancer cell line. Among 2,3-dehydrosilibinin derivatives, 7-O-methyl-2,3-dehydrosilibinin (10) and 7-O-ethyl-2,3-dehydrosilibinin (11) have been identified as the optimal compounds with the highest potency towards both androgen-dependent LNCaP and androgen-independent PC-3 prostate cancer cell lines. 7-O-Ethyl-2,3-dehydrosilibinin (11) was demonstrated to arrest PC-3 cell cycle at the G0/G1 phase and to induce PC-3 cell apoptosis. The findings in this study suggest that antiproliferative potency of silibinin and 2,3-dehydrosilibinin can be appreciably enhanced through suitable chemical modifications on the phenolic hydroxyl group at C-7 and that introduction of a chemical moiety with the potential to improve bioavailability through a linker to 7-OH in silibinin and 2,3-dehydrosilibinin would be a feasible strategy for the development of silibinin derivatives as anti-prostate cancer agents. Published by Elsevier Masson SAS.
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NASA Astrophysics Data System (ADS)
Lee, Sehan; Barron, Mace G.
2016-04-01
Organophosphate (OP) and carbamate esters can inhibit acetylcholinesterase (AChE) by binding covalently to a serine residue in the enzyme active site, and their inhibitory potency depends largely on affinity for the enzyme and the reactivity of the ester. Despite this understanding, there has been no mechanism-based in silico approach for classification and prediction of the inhibitory potency of ether OPs or carbamates. This prompted us to develop a three dimensional prediction framework for OPs, carbamates, and their analogs. Inhibitory structures of a compound that can form the covalent bond were identified through analysis of docked conformations of the compound and its metabolites. Inhibitory potencies of the selected structures were then predicted using a previously developed three dimensional quantitative structure-active relationship. This approach was validated with a large number of structurally diverse OP and carbamate compounds encompassing widely used insecticides and structural analogs including OP flame retardants and thio- and dithiocarbamate pesticides. The modeling revealed that: (1) in addition to classical OP metabolic activation, the toxicity of carbamate compounds can be dependent on biotransformation, (2) OP and carbamate analogs such as OP flame retardants and thiocarbamate herbicides can act as AChEI, (3) hydrogen bonds at the oxyanion hole is critical for AChE inhibition through the covalent bond, and (4) π-π interaction with Trp86 is necessary for strong inhibition of AChE. Our combined computation approach provided detailed understanding of the mechanism of action of OP and carbamate compounds and may be useful for screening a diversity of chemical structures for AChE inhibitory potency.
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Savić Vujović, Katarina R; Vučković, Sonja; Srebro, Dragana; Ivanović, Milovan; Došen-Mićović, Ljiljana; Vučetić, Čedomir; Džoljić, Eleonora; Prostran, Milica
2013-04-01
In addition to producing antinociception, opioids exert profound effects on body temperature. This study aimed at comparing antinociceptive and hyperthermic responses between two groups of μ-opioid receptor agonists: fentanyl (4-anilinopiperidine-type) and morphine (phenanthrene-type) derivatives in rats. Analgesic activity was assessed by tail immersion test and the body temperature by insertion of a thermometer probe into the colon. Fentanyl (F), (±)-cis-3-methyl fentanyl (CM), (±)-cis-3-carbomethoxy fentanyl (C), (±)trans-3-carbomethoxy fentanyl (T) and (±)-cis-3 butyl fentanyl (B) produced dose-dependent increase in antinociception and hyperthermia. The relative order of analgesic potency was: CM(11.27)>F(1)>C(0.35)≥T(0.11)≥B(0.056). Similar to this, the relative order of hyperthermic potency was: CM(8.43)>F(1)>C(0.46)≥T(0.11)≥B(0.076). Morphine (M), oxycodone (O), thebacon (T) and 6,14-ethenomorphinan-7-methanol, 4,5-epoxy-6-fluoro-3-hydroxy-α,α,17-trimethyl-, (5α,7α) (E) also produced dose-dependent increase in antinociception and hyperthermia. Among morphine derivatives the relative order of analgesic potency was: E(56)>O(5)≥T(2.6)>M(1), and similar to this, the relative order of hyperthermic potency was: E(37)>O(3)≥T(2.3)>M(1). Morphine (phenanthrene-type) and fentanyl (4-anilinopiperidine-type) derivatives produced hyperthermia in rats at doses about 2 times lower, and 6-11 times higher, than their median antinociceptive doses, respectively. This study is first to identify difference between these two classes of opioid drugs in their potencies in producing hyperthermia. Further studies are needed to clarify the significance of these findings.
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Erectile Function Durability Following Permanent Prostate Brachytherapy
DOE Office of Scientific and Technical Information (OSTI.GOV)
Taira, Al V.; Merrick, Gregory S., E-mail: gmerrick@urologicresearchinstitute.or; Galbreath, Robert W.
2009-11-01
Purpose: To evaluate long-term changes in erectile function following prostate brachytherapy. Methods and Materials: This study included 226 patients with prostate cancer and preimplant erectile function assessed by the International Index of Erectile Function-6 (IIEF-6) who underwent brachytherapy in two prospective randomized trials between February 2001 and January 2003. Median follow-up was 6.4 years. Pre- and postbrachytherapy potency was defined as IIEF-6 >= 13 without pharmacologic or mechanical support. The relationship among clinical, treatment, and dosimetric parameters and erectile function was examined. Results: The 7-year actuarial rate of potency preservation was 55.6% with median postimplant IIEF of 22 in potentmore » patients. Potent patients were statistically younger (p = 0.014), had a higher preimplant IIEF (p < 0.001), were less likely to be diabetic (p = 0.002), and were more likely to report nocturnal erections (p = 0.008). Potency preservation in men with baseline IIEF scores of 29-30, 24-28, 18-23, and 13-17 were 75.5% vs. 73.6%, 51.7% vs. 44.8%, 48.0% vs. 40.0%, and 23.5% vs. 23.5% in 2004 vs. 2008. In multivariate Cox regression analysis, preimplant IIEF, hypertension, diabetes, prostate size, and brachytherapy dose to proximal penis strongly predicted for potency preservation. Impact of proximal penile dose was most pronounced for men with IIEF of 18-23 and aged 60-69. A significant minority of men who developed postimplant impotence ultimately regained erectile function. Conclusion: Potency preservation and median IIEF scores following brachytherapy are durable. Thoughtful dose sparing of proximal penile structures and early penile rehabilitation may further improve these results.« less
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Chen, Ronald JY; Chung, Tse-yu; Li, Feng-yin; Yang, Wei-hung; Jinn, Tzyy-rong; Tzen, Jason TC
2010-01-01
Aim: To examine if steroid-like compounds found in many Chinese medicinal products conventionally used for the promotion of blood circulation may act as active components via the same molecular mechanism triggered by cardiac glycosides, such as ouabain. Methods: The inhibitory potency of ouabain and the identified steroid-like compounds on Na+/K+-ATPase activity was examined and compared. Molecular modeling was exhibited for the docking of these compounds to Na+/K+-ATPase. Results: All the examined steroid-like compounds displayed more or less inhibition on Na+/K+-ATPase, with bufalin (structurally almost equivalent to ouabain) exhibiting significantly higher inhibitory potency than the others. In the pentacyclic triterpenoids examined, ursolic acid and oleanolic acid were moderate inhibitors of Na+/K+-ATPase, and their inhibitory potency was comparable to that of ginsenoside Rh2. The relatively high inhibitory potency of ursolic acid or oleanolic acid was due to the formation of a hydrogen bond between its carboxyl group and the Ile322 residue in the deep cavity close to two K+ binding sites of Na+/K+-ATPase. Moreover, the drastic difference observed in the inhibitory potency of ouabain, bufalin, ginsenoside Rh2, and pentacyclic triterpenoids is ascribed mainly to the number of hydrogen bonds and partially to the strength of hydrophobic interaction between the compounds and residues around the deep cavity of Na+/K+-ATPase. Conclusion: Steroid-like compounds seem to contribute to therapeutic effects of many cardioactive Chinese medicinal products. Chinese herbs, such as Prunella vulgaris L, rich in ursolic acid, oleanolic acid and their glycoside derivatives may be adequate sources for cardiac therapy via effective inhibition on Na+/K+-ATPase. PMID:20523340
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Burton, J H; Stanley, S D; Knych, H K; Rodriguez, C O; Skorupski, K A; Rebhun, R B
2016-01-01
Compounded lomustine is used commonly in veterinary patients. However, the potential variability in these formulations is unknown and concern exists that compounded formulations of drugs may differ in potency from Food and Drug Administration (FDA)-approved products. The initial objective of this study was to evaluate the frequency and severity of neutropenia in dogs treated with compounded or FDA-approved formulations of lomustine. Subsequent analyses aimed to determine the potency of lomustine obtained from several compounding pharmacies. Thirty-seven dogs treated with FDA-approved or compounded lomustine. Dogs that received compounded or FDA-approved lomustine and had pretreatment and nadir CBCs performed were eligible for inclusion. Variables assessed included lomustine dose, neutrophil counts, and severity of neutropenia. Lomustine 5 mg capsules from 5 compounding sources were tested for potency using high-pressure liquid chromatography (HPLC) with ultraviolet (UV) detection. Twenty-one dogs received FDA-approved lomustine and 16 dogs were treated with lomustine prescribed from a single compounding pharmacy. All dogs treated with FDA-approved lomustine were neutropenic after treatment; 15 dogs (71%) developed grade 3 or higher neutropenia. Four dogs (25%) given compounded lomustine became neutropenic, with 2 dogs (12.5%) developing grade 3 neutropenia. The potency of lomustine from 5 compounding pharmacies ranged from 50 to 115% of the labeled concentration, with 1 sample within ±10% of the labeled concentration. These data support broader investigation into the potency and consistency of compounded chemotherapy drugs and highlight the potential need for greater oversight of these products. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.
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Smith, Heidi L; Cheslock, Peter; Leney, Mark; Barton, Bruce; Molrine, Deborah C
2016-08-17
Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving ≥ 27.5 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg S315/IU DAT (95% CI 16-21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 µg/IU (95% CI 38-59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans.
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Bartlett, M S; Shaw, M; Navaran, P; Smith, J W; Queener, S F
1995-11-01
Many antifolates are known to inhibit dihydrofolate reductase from murine Pneumocystis carinii, with 50% inhibitory concentrations (IC50s) ranging from 10(-4) to 10(-11) M. The relationship of the potency against isolated enzyme to the potency against intact murine P. carinii cells was explored with 17 compounds that had proven selectivity for or potency against P. carinii dihydrofolate reductase. Pyrimethamine and one analog were inhibitory to P. carinii in culture at concentrations two to seven times the IC50s for the enzyme, suggesting that the compounds may enter P. carinii cells in culture. Methotrexate was a potent inhibitor of P. carinii dihydrofolate reductase, but the concentrations effective in culture were more than 1,000-fold higher than IC50s for the enzyme, since P. carinii lacks an uptake system for methotrexate. Analogs of methotrexate in which chlorine, bromine, or iodine was added to the phenyl ring had improved potency against the isolated enzyme but were markedly less effective in culture; polyglutamation also lowered the activity in culture but improved activity against the enzyme. Substitution of a naphthyl group for the phenyl group of methotrexate produced a compound with improved activity against the enzyme (IC50, 0.00019 microM) and excellent activity in culture (IC50, 0.1 microM). One trimetrexate analog in which an aspartate or a chlorine replaced two of the methoxy groups of trimetrexate was much more potent and was much more selective toward P. carinii dihydrofolate reductase than trimetrexate; this analog was also as active as trimetrexate in culture. These studies suggest that modifications of antifolate structures can be made that facilitate activity against intact organisms while maintaining the high degrees of potency and the selectivities of the agents can be made.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Mundy, Lukas J.; Environment Canada, National Wildlife Research Centre, Ottawa, Ontario; Jones, Stephanie P.
Some uncertainty exists regarding the purity of hexachlorobenzene (HCB) used in past toxicity studies. It has been suggested that reported toxic and biochemical effects initially attributed to HCB exposure may have actually been elicited by contamination of HCB by polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). Herein, primary cultures of chicken embryo hepatocytes (CEH) were used to compare the potencies of two lots of reagent-grade hexachlorobenzene (HCB-old [HCB-O] and HCB-new [HCB-N]), highly purified HCB (HCB-P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as inducers of ethoxyresorufin O-deethylase (EROD) activity, cytochrome P4501A4 (CYP1A4) messenger ribonucleic acid (mRNA) and CYP1A5 mRNA. The study also compared themore » EROD- and CYP1A4/5 mRNA-inducing potencies of HCB to the potencies of two mono-ortho substituted polychlorinated biphenyls (PCBs), 2,3,3',4,4'-pentachlorobiphenyl (PCB 105) and 2,3'4,4',5-pentachlorobiphenyl (PCB 118). HCB-O, HCB-N and HCB-P all induced EROD activity and up-regulated CYP1A4 and CYP1A5 mRNAs. Induction was not caused by contamination of HCB with PCDDs or PCDFs. Based upon a comparison of the EC{sub 50} and EC{sub threshold} values for EROD and CYP1A4/5 mRNA concentration-response curves, the potency of HCB relative to the potency of TCDD was 0.0001, and was similar to that of PCB 105 and PCB 118. The maximal EROD activity and CYP1A4/5 mRNA expression differed greatly between HCB and TCDD, and may contribute to an overestimation of the ReP value calculated for highly purified HCB.« less
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Majewsky, Vera; Scherr, Claudia; Arlt, Sebastian Patrick; Kiener, Jonas; Frrokaj, Kristina; Schindler, Tobias; Klocke, Peter; Baumgartner, Stephan
2014-04-01
Reproducibility of basic research investigations in homeopathy is challenging. This study investigated if formerly observed effects of homeopathically potentised gibberellic acid (GA3) on growth of duckweed (Lemna gibba L.) were reproducible. Duckweed was grown in potencies (14x-30x) of GA3 and one time succussed and unsuccussed water controls. Outcome parameter area-related growth rate was determined by a computerised image analysis system. Three series including five independent blinded and randomised potency experiments (PE) each were carried out. System stability was controlled by three series of five systematic negative control (SNC) experiments. Gibbosity (a specific growth state of L. gibba) was investigated as possibly essential factor for reactivity of L. gibba towards potentised GA3 in one series of potency and SNC experiments, respectively. Only in the third series with gibbous L. gibba L. we observed a significant effect (p = 0.009, F-test) of the homeopathic treatment. However, growth rate increased in contrast to the former study, and most biologically active potency levels differed. Variability in PE was lower than in SNC experiments. The stability of the experimental system was verified by the SNC experiments. Gibbosity seems to be a necessary condition for reactivity of L. gibba to potentised GA3. Further still unknown conditions seem to govern effect direction and the pattern of active and inactive potency levels. When designing new reproducibility studies, the physiological state of the test organism must be considered. Variability might be an interesting parameter to investigate effects of homeopathic remedies in basic research. Copyright © 2014 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.
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Can biochemistry drive drug discovery beyond simple potency measurements?
Chène, Patrick
2012-04-01
Among the fields of expertise required to develop drugs successfully, biochemistry holds a key position in drug discovery at the interface between chemistry, structural biology and cell biology. However, taking the example of protein kinases, it appears that biochemical assays are mostly used in the pharmaceutical industry to measure compound potency and/or selectivity. This limited use of biochemistry is surprising, given that detailed biochemical analyses are commonly used in academia to unravel molecular recognition processes. In this article, I show that biochemistry can provide invaluable information on the dynamics and energetics of compound-target interactions that cannot be obtained on the basis of potency measurements and structural data. Therefore, an extensive use of biochemistry in drug discovery could facilitate the identification and/or development of new drugs. Copyright © 2012 Elsevier Ltd. All rights reserved.
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Novel orally active growth hormone secretagogues.
Hansen, T K; Ankersen, M; Hansen, B S; Raun, K; Nielsen, K K; Lau, J; Peschke, B; Lundt, B F; Thøgersen, H; Johansen, N L; Madsen, K; Andersen, P H
1998-09-10
A novel class of growth hormone-releasing compounds with a molecular weight in the range from 500 to 650 has been discovered. The aim of this study was to obtain growth hormone secretagogues with oral bioavailability. By a rational approach we were able to reduce the size of the lead compound ipamorelin (4) and simultaneously to reduce hydrogen-bonding potential by incorporation of backbone isosters while retaining in vivo potency in swine. A rat pituitary assay was used for screening of all compounds and to evaluate which compounds should be tested further for in vivo potency in swine and oral bioavailability, fpo, in dogs. Most of the tested compounds had fpo in the range of 10-55%. In vivo potency in swine after iv dosing is reported, and ED50 was found to be 30 nmol/kg of body weight for the most potent compound.
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A comparative study of warheads for design of cysteine protease inhibitors.
Silva, Daniel G; Ribeiro, Jean F R; De Vita, Daniela; Cianni, Lorenzo; Franco, Caio Haddad; Freitas-Junior, Lucio H; Moraes, Carolina Borsoi; Rocha, Josmar R; Burtoloso, Antonio C B; Kenny, Peter W; Leitão, Andrei; Montanari, Carlos A
2017-11-15
The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the α methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Negative inotropism of terpenes on guinea pig left atrium: structure-activity relationships.
Vasconcelos, Carla M L; Oliveira, Ingrid S N; Santos, José N A; Souza, Américo A; Menezes-Filho, José E R; Silva Neto, Júlio A; Lima, Tamires C; de Sousa, Damião P
2018-06-01
The aim of this work was to evaluate the pharmacological effect of seven structurally related terpenes on the contractility of cardiac muscle. The effect of terpenes was studied on isolated electrically driven guinea pig left atrium. From concentration-response curves for inotropic effect were determined the EC 50 and relative potency of such terpenes. Our results revealed that all terpenes, except phytol, showed ability to reduce the contractile response of guinea pig left atrium. Further, relative potency was directly related to the number of isoprene units and to the lipophilicity of the compounds. For example, sesquiterpenes farnesol and nerolidol showed higher relative potency when compared with the monoterpenes citronellol, geraniol and nerol. We can conclude that most of the evaluated terpenes showed a promising negative inotropism on the atrial muscle. Future studies are necessary to investigate their action mechanism.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Sloman, David L.; Noucti, Njamkou; Altman, Michael D.
Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer’s disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility.
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In vitro estrogen receptor assays are valuable screening tools for identifying environmental samples and chemicals that display estrogenic activity. However, in vitro potency cannot necessarily be extrapolated to estimates of in vivo potency because in vitro assays are currently...
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1994-02-01
dextromethorphan (014, [+J-3-aethyl-l7-methylmorphinan) may be, in part, due to its ____________________metabolism to the PCP-like compound... Dextromethorphan : Improved Efficacy, Potency, Duration and Side-Effect Profile1 FRANK C. TORTELLA, LYDIA ROBLES, JEFFREY M. WITKIN and AMY HAUCK NEWMAN... dextromethorphan ; NMDA, N-methyl-D-aspartate; PCP, phencyclidine hydrochloride; DX, dextrorphan; AHN649, [(+)-3- amino-1 7-methylmorphinan]; AHN1 -036
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Arylimidamide-Azole Combinations Against Leishmaniasis
2015-09-01
potency of posaconazole in an amastigote macrophage assay2, the only azole to demonstrate activity in vitro against CL species, showed variable activity ...ranging from no activity observed against L. panamensis and L. guyanensis to modest activity against L. tropica to potent activity against L. major...species, and the potency is variable; while posaconazole is active against Old World CL species such as L. major and L. tropica it is not active
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Occurrence and potential causes of androgenic activities in source and drinking water in China.
Hu, Xinxin; Shi, Wei; Wei, Si; Zhang, Xiaowei; Feng, Jianfang; Hu, Guanjiu; Chen, Sulan; Giesy, John P; Yu, Hongxia
2013-09-17
The increased incidences of disorders of male reproductive tract as well as testicular and prostate cancers have been attributed to androgenic pollutants in the environment. Drinking water is one pathway of exposure through which humans can be exposed. In this study, both potencies of androgen receptor (AR) agonists and antagonists were determined in organic extracts of raw source water as well as finished water from waterworks, tap water, boiled water, and poured boiled water in eastern China. Ten of 13 samples of source water exhibited detectable AR antagonistic potencies with AR antagonist equivalents (Ant-AR-EQs) ranging from <15.3 (detection limit) to 140 μg flutamide/L. However, no AR agonistic activity was detected in any source water. All finished water from waterworks, tap water, boiled water, and poured boiled water exhibited neither AR agonistic nor antagonistic activity. Although potential risks are posed by source water, water treatment processes effectively removed AR antagonists. Boiling and pouring of water further removed these pollutants. Phthalate esters (PAEs) including diisobutyl phthalate (DIBP) and dibutyl phthalate (DBP) were identified as major contributors to AR antagonistic potencies in source waters. Metabolites of PAEs exhibited no AR antagonistic activity and did not increase potencies of PAEs when they coexist.
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Epoxy resin monomers with reduced skin sensitizing potency.
O'Boyle, Niamh M; Niklasson, Ida B; Tehrani-Bagha, Ali R; Delaine, Tamara; Holmberg, Krister; Luthman, Kristina; Karlberg, Ann-Therese
2014-06-16
Epoxy resin monomers (ERMs), especially diglycidyl ethers of bisphenol A and F (DGEBA and DGEBF), are extensively used as building blocks for thermosetting polymers. However, they are known to commonly cause skin allergy. This research describes a number of alternative ERMs, designed with the aim of reducing the skin sensitizing potency while maintaining the ability to form thermosetting polymers. The compounds were designed, synthesized, and assessed for sensitizing potency using the in vivo murine local lymph node assay (LLNA). All six epoxy resin monomers had decreased sensitizing potencies compared to those of DGEBA and DGEBF. With respect to the LLNA EC3 value, the best of the alternative monomers had a value approximately 2.5 times higher than those of DGEBA and DGEBF. The diepoxides were reacted with triethylenetetramine, and the polymers formed were tested for technical applicability using thermogravimetric analysis and differential scanning calorimetry. Four out of the six alternative ERMs gave polymers with a thermal stability comparable to that obtained with DGEBA and DGEBF. The use of improved epoxy resin monomers with less skin sensitizing effects is a direct way to tackle the problem of contact allergy to epoxy resin systems, particularly in occupational settings, resulting in a reduction in the incidence of allergic contact dermatitis.
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Comparative sensitizing potencies of fragrances, preservatives, and hair dyes.
Lidén, Carola; Yazar, Kerem; Johansen, Jeanne D; Karlberg, Ann-Therese; Uter, Wolfgang; White, Ian R
2016-11-01
The local lymph node assay (LLNA) is used for assessing sensitizing potential in hazard identification and risk assessment for regulatory purposes. Sensitizing potency on the basis of the LLNA is categorized into extreme (EC3 value of ≤0.2%), strong (>0.2% to ≤2%), and moderate (>2%). To compare the sensitizing potencies of fragrance substances, preservatives, and hair dye substances, which are skin sensitizers that frequently come into contact with the skin of consumers and workers, LLNA results and EC3 values for 72 fragrance substances, 25 preservatives and 107 hair dye substances were obtained from two published compilations of LLNA data and opinions by the Scientific Committee on Consumer Safety and its predecessors. The median EC3 values of fragrances (n = 61), preservatives (n = 19) and hair dyes (n = 59) were 5.9%, 0.9%, and 1.3%, respectively. The majority of sensitizing preservatives and hair dyes are thus strong or extreme sensitizers (EC3 value of ≤2%), and fragrances are mostly moderate sensitizers. Although fragrances are typically moderate sensitizers, they are among the most frequent causes of contact allergy. This indicates that factors other than potency need to be addressed more rigorously in risk assessment and risk management. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
McComas, Casey C.; Palani, Anandan; Chang, Wei
Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants. Ultimately, a biology and medicinalmore » chemistry collaboration led to the discovery of the development candidate MK-8876. MK-8876 demonstrated a pan-genotypic potency profile and maintained potency against clinically relevant mutants. It demonstrated moderate bioavailability in rats and dogs, but showed low plasma clearance characteristics consistent with once-daily dosing. Herein we describe the efforts which led to the discovery of MK-8876, which advanced into Phase 1 monotherapy studies for evaluation and characterization as a component of an all-oral direct-acting drug regimen for the treatment of chronic HCV infection.« less
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Potency testing of veterinary vaccines: the way from in vivo to in vitro.
Romberg, Judith; Lang, Stefan; Balks, Elisabeth; Kamphuis, Elisabeth; Duchow, Karin; Loos, Daniela; Rau, Henriette; Motitschke, Andreas; Jungbäck, Carmen
2012-01-01
Current quality control of inactivated animal vaccines still focuses on the potency of final products in a batch-wise manner. Animal welfare concerns as well as scientific considerations have led to the '3Rs-concept' that comprises the refinement of animal procedures, the reduction of animal numbers, and the replacement of animal models. Although the 3Rs-concept has been widely accepted as a fundamental principle, the number of approved alternatives for in vivo tests is still limited. To promote further progress, the international scientific workshop 'Potency Testing of Veterinary Vaccines: The Way from in vivo to in vitro' was held at the Paul-Ehrlich-Institut in Langen, Germany, on 01-03 December 2010. More than 130 participants from industry, academia and regulatory authorities discussed the current state of the 3Rs-concept, examples of its successful implementation as well as still existing hurdles. Special emphasis was laid on the 'consistency approach' that aims to ensure relevant quality attributes of vaccine batches by in vitro analyses during production rather than by in vivo potency tests on the final product. This report provides an overview of the insights gained, including the recommendations produced at the end of the workshop. Copyright © 2011. Published by Elsevier Ltd.. All rights reserved.
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[Urodynamics foundations: contractile potency and urethral doppler].
Benítez Navío, Julio; Caballero Gómez, Pilar; Delgado Elipe, Ildefonso
2002-12-01
To calculate the bladder softening factor, elastic constant and contractile potency. For the analysis we considered bladder behavior like that of a spring. See articles 1 and 2 published in this issue. Using flowmetry, Doppler ultrasound and abdominal pressure (Transrectal pressure register catheter) an analytical solution that permits calculation of factors defining bladder behavior was looked for. Doppler ultrasound allows us to know urine velocity through the prostatic urethra and, therefore, to calculate bladder contractile potency. Equations are solved reaching an analytical solution that allows calculating those factors that define bladder behavior: Bladder contractile potency, detrusor elastic constant, considering it behaves like a spring, and calculation of muscle resistance to movement. All thanks to Doppler ultrasound that allows to know urine speed. The bladder voiding phase is defined with the aforementioned factors; storage phase behavior can be indirectly inferred. Only uroflowmetry curves, Doppler ultrasound and abdominal pressure value are used. We comply with the so called non invasive urodynamics although for us it is just another phase in the biomechanical study of the detrusor muscle. Main conclusion is the addition of Doppler ultrasound to the urodynamist armamentarium as an essential instrument for the comprehension of bladder dynamics and calculation of bladder behavior defining factors. It is not a change in the focus but in the methods, gaining knowledge and diminishing invasion.
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NASA Astrophysics Data System (ADS)
Amos, Sarah-Beth T. A.; Vermeer, Louic S.; Ferguson, Philip M.; Kozlowska, Justyna; Davy, Matthew; Bui, Tam T.; Drake, Alex F.; Lorenz, Christian D.; Mason, A. James
2016-11-01
The interaction of antimicrobial peptides (AMPs) with the inner membrane of Gram-negative bacteria is a key determinant of their abilities to exert diverse bactericidal effects. Here we present a molecular level understanding of the initial target membrane interaction for two cationic α-helical AMPs that share structural similarities but have a ten-fold difference in antibacterial potency towards Gram-negative bacteria. The binding and insertion from solution of pleurocidin or magainin 2 to membranes representing the inner membrane of Gram-negative bacteria, comprising a mixture of 128 anionic and 384 zwitterionic lipids, is monitored over 100 ns in all atom molecular dynamics simulations. The effects of the membrane interaction on both the peptide and lipid constituents are considered and compared with new and published experimental data obtained in the steady state. While both magainin 2 and pleurocidin are capable of disrupting bacterial membranes, the greater potency of pleurocidin is linked to its ability to penetrate within the bacterial cell. We show that pleurocidin displays much greater conformational flexibility when compared with magainin 2, resists self-association at the membrane surface and penetrates further into the hydrophobic core of the lipid bilayer. Conformational flexibility is therefore revealed as a key feature required of apparently α-helical cationic AMPs for enhanced antibacterial potency.
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NASA Astrophysics Data System (ADS)
Ghobadloo, Shahrokh M.; Balcerzak, Anna K.; Gargaun, Ana; Muharemagic, Darija; Mironov, Gleb G.; Capicciotti, Chantelle J.; Briard, Jennie G.; Ben, Robert N.; Berezovski, Maxim V.
2014-07-01
The inability of vaccines to retain sufficient thermostability has been an obstacle to global vaccination programs. To address this major limitation, we utilized carbohydrate-based ice recrystallization inhibitors (IRIs) to eliminate the cold chain and stabilize the potency of Vaccinia virus (VV), Vesicular Stomatitis virus (VSV) and Herpes virus-1 (HSV-1). The impact of these IRIs was tested on the potency of the viral vectors using a plaque forming unit assay following room temperature storage, cryopreservation with successive freeze-thaw cycles and lyophilization. Viral potency after storage with all three conditions demonstrated that N-octyl-gluconamide (NOGlc) recovered the infectivity of shelf stored VV, 5.6 Log10 PFU mL-1 during 40 days, and HSV-1, 2.7 Log10 PFU mL-1 during 9 days. Carbon-linked antifreeze glycoprotein analogue ornithine-glycine-glycine-galactose (OGG-Gal) increases the recovery of VV and VSV more than 1 Log10 PFU mL-1 after 10 freeze-thaw cycles. In VSV, cryostorage with OGG-Gal maintains high infectivity and reduces temperature-induced aggregation of viral particles by 2 times that of the control. In total, OGG-Gal and NOGlc preserve virus potency during cryostorage. Remarkably, NOGlc has potential to eliminate the cold chain and permit room temperature storage of viral vectors.
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Ueda, I; Yamanaka, M
1997-04-01
Anesthetic potency increases at lower temperatures. In contrast, the transfer enthalpy of volatile anesthetics from water to macromolecules is usually positive. The transfer decreases at lower temperature. It was proposed that a few selective proteins bind volatile anesthetics with negative delta H, and these proteins are involved in signal transduction. There has been no report on direct estimation of binding delta H of anesthetics to proteins. This study used isothermal titration calorimetry to analyze chloroform binding to bovine serum albumin. The calorimetrically measured delta H cal was -10.37 kJ.mol-1. Thus the negative delta H of anesthetic binding is not limited to signal transduction proteins. The binding was saturable following Fermi-Dirac statistics and is characterized by the Langmuir adsorption isotherms, which is interfacial. The high-affinity association constant, K, was 2150 +/- 132 M-1 (KD = 0.47 mM) with the maximum binding number, Bmax = 3.7 +/- 0.2. The low-affinity K was 189 +/- 3.8 M-1 (KD = 5.29 mM), with a Bmax of 13.2 +/- 0.3. Anesthetic potency is a function of the activity of anesthetic molecules, not the concentration. Because the sign of delta H determines the temperature dependence of distribution of anesthetic molecules, it is irrelevant to the temperature dependence of anesthetic potency.
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Ueda, I; Yamanaka, M
1997-01-01
Anesthetic potency increases at lower temperatures. In contrast, the transfer enthalpy of volatile anesthetics from water to macromolecules is usually positive. The transfer decreases at lower temperature. It was proposed that a few selective proteins bind volatile anesthetics with negative delta H, and these proteins are involved in signal transduction. There has been no report on direct estimation of binding delta H of anesthetics to proteins. This study used isothermal titration calorimetry to analyze chloroform binding to bovine serum albumin. The calorimetrically measured delta H cal was -10.37 kJ.mol-1. Thus the negative delta H of anesthetic binding is not limited to signal transduction proteins. The binding was saturable following Fermi-Dirac statistics and is characterized by the Langmuir adsorption isotherms, which is interfacial. The high-affinity association constant, K, was 2150 +/- 132 M-1 (KD = 0.47 mM) with the maximum binding number, Bmax = 3.7 +/- 0.2. The low-affinity K was 189 +/- 3.8 M-1 (KD = 5.29 mM), with a Bmax of 13.2 +/- 0.3. Anesthetic potency is a function of the activity of anesthetic molecules, not the concentration. Because the sign of delta H determines the temperature dependence of distribution of anesthetic molecules, it is irrelevant to the temperature dependence of anesthetic potency. PMID:9083685
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Reduction of animal suffering in rabies vaccine potency testing by introduction of humane endpoints.
Takayama-Ito, Mutsuyo; Lim, Chang-Kweng; Nakamichi, Kazuo; Kakiuchi, Satsuki; Horiya, Madoka; Posadas-Herrera, Guillermo; Kurane, Ichiro; Saijo, Masayuki
2017-03-01
Potency controls of inactivated rabies vaccines for human use are confirmed by the National Institutes of Health challenge test in which lethal infection with severe neurological symptoms should be observed in approximately half of the mice inoculated with the rabies virus. Weight loss, decreased body temperature, and the presence of rabies-associated neurological signs have been proposed as humane endpoints. The potential for reduction of animal suffering by introducing humane endpoints in the potency test for inactivated rabies vaccine for human use was investigated. The clinical signs were scored and body weight was monitored. The average times to death following inoculation were 10.49 and 10.99 days post-inoculation (dpi) by the potency and challenge control tests, respectively, whereas the average times to showing Score-2 signs (paralysis, trembling, and coma) were 6.26 and 6.55 dpi, respectively. Body weight loss of more than 15% appeared at 5.82 and 6.42 dpi. The data provided here support the introduction of obvious neuronal signs combined with a body weight loss of ≥15% as a humane endpoint to reduce the time of animal suffering by approximately 4 days. Copyright © 2017 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.
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Potency factors for risk assessment at Libby, Montana.
Moolgavkar, Suresh H; Turim, Jay; Alexander, Dominik D; Lau, Edmund C; Cushing, Colleen A
2010-08-01
We reanalyzed the Libby vermiculite miners' cohort assembled by Sullivan to estimate potency factors for lung cancer, mesothelioma, nonmalignant respiratory disease (NMRD), and all-cause mortality associated with exposure to Libby fibers. Our principal statistical tool for analyses of lung cancer, NMRD, and total mortality in the cohort was the time-dependent proportional hazards model. For mesothelioma, we used an extension of the Peto formula. For a cumulative exposure to Libby fiber of 100 f/mL-yr, our estimates of relative risk (RR) are as follows: lung cancer, RR = 1.12, 95% confidence interval (CI) =[1.06, 1.17]; NMRD, RR = 1.14, 95% CI =[1.09, 1.18]; total mortality, RR = 1.06, 95% CI =[1.04, 1.08]. These estimates were virtually identical when analyses were restricted to the subcohort of workers who were employed for at least one year. For mesothelioma, our estimate of potency is K(M) = 0.5 x 10(-8), 95% CI =[0.3 x 10(-8), 0.8 x 10(-8)]. Finally, we estimated the mortality ratios standardized against the U.S. population for lung cancer, NMRD, and total mortality and obtained estimates that were in good agreement with those reported by Sullivan. The estimated potency factors form the basis for a quantitative risk assessment at Libby.
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Alcohol's Effects on Lipid Bilayer Properties
Ingólfsson, Helgi I.; Andersen, Olaf S.
2011-01-01
Alcohols are known modulators of lipid bilayer properties. Their biological effects have long been attributed to their bilayer-modifying effects, but alcohols can also alter protein function through direct protein interactions. This raises the question: Do alcohol's biological actions result predominantly from direct protein-alcohol interactions or from general changes in the membrane properties? The efficacy of alcohols of various chain lengths tends to exhibit a so-called cutoff effect (i.e., increasing potency with increased chain length, which that eventually levels off). The cutoff varies depending on the assay, and numerous mechanisms have been proposed such as: limited size of the alcohol-protein interaction site, limited alcohol solubility, and a chain-length-dependent lipid bilayer-alcohol interaction. To address these issues, we determined the bilayer-modifying potency of 27 aliphatic alcohols using a gramicidin-based fluorescence assay. All of the alcohols tested (with chain lengths of 1–16 carbons) alter the bilayer properties, as sensed by a bilayer-spanning channel. The bilayer-modifying potency of the short-chain alcohols scales linearly with their bilayer partitioning; the potency tapers off at higher chain lengths, and eventually changes sign for the longest-chain alcohols, demonstrating an alcohol cutoff effect in a system that has no alcohol-binding pocket. PMID:21843475
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Stajkovic, Alexander D; Lee, Dongseop; Nyberg, Anthony J
2009-05-01
The authors examined relationships among collective efficacy, group potency, and group performance. Meta-analytic results (based on 6,128 groups, 31,019 individuals, 118 correlations adjusted for dependence, and 96 studies) reveal that collective efficacy was significantly related to group performance (.35). In the proposed nested 2-level model, collective efficacy assessment (aggregation and group discussion) was tested as the 1st-level moderator. It showed significantly different average correlations with group performance (.32 vs. .45), but the group discussion assessment was homogeneous, whereas the aggregation assessment was heterogeneous. Consequently, there was no 2nd-level moderation for the group discussion, and heterogeneity in the aggregation group was accounted for by the 2nd-level moderator, task interdependence (high, moderate, and low levels were significant; the higher the level, the stronger the relationship). The 2nd and 3rd meta-analyses indicated that group potency was related to group performance (.29) and to collective efficacy (.65). When tested in a structural equation modeling analysis based on meta-analytic findings, collective efficacy fully mediated the relationship between group potency and group performance. The authors suggest future research and convert their findings to a probability of success index to help facilitate practice. (c) 2009 APA, all rights reserved.
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Handa, Koichi; Nakagome, Izumi; Yamaotsu, Noriyuki; Gouda, Hiroaki; Hirono, Shuichi
2015-01-01
The pregnane X receptor [PXR (NR1I2)] induces the expression of xenobiotic metabolic genes and transporter genes. In this study, we aimed to establish a computational method for quantifying the enzyme-inducing potencies of different compounds via their ability to activate PXR, for the application in drug discovery and development. To achieve this purpose, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) for predicting enzyme-inducing potencies, based on computer-ligand docking to multiple PXR protein structures sampled from the trajectory of a molecular dynamics simulation. Molecular mechanics-generalized born/surface area scores representing the ligand-protein-binding free energies were calculated for each ligand. As a result, the predicted enzyme-inducing potencies for compounds generated by the CoMFA model were in good agreement with the experimental values. Finally, we concluded that this 3D-QSAR model has the potential to predict the enzyme-inducing potencies of novel compounds with high precision and therefore has valuable applications in the early stages of the drug discovery process. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.
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Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia.
Garami, Andras; Shimansky, Yury P; Pakai, Eszter; Oliveira, Daniela L; Gavva, Narender R; Romanovsky, Andrej A
2010-01-27
Transient receptor potential vanilloid-1 (TRPV1) antagonists are widely viewed as next-generation pain therapeutics. However, these compounds cause hyperthermia, a serious side effect. TRPV1 antagonists differentially block three modes of TRPV1 activation: by heat, protons, and chemical ligands (e.g., capsaicin). We asked what combination of potencies in these three modes of TRPV1 activation corresponds to the lowest potency of a TRPV1 antagonist to cause hyperthermia. We studied hyperthermic responses of rats, mice, and guinea pigs to eight TRPV1 antagonists with different pharmacological profiles and used mathematical modeling to find a relative contribution of the blockade of each activation mode to the development of hyperthermia. We found that the hyperthermic effect has the highest sensitivity to the extent of TRPV1 blockade in the proton mode (0.43 to 0.65) with no to moderate sensitivity in the capsaicin mode (-0.01 to 0.34) and no sensitivity in the heat mode (0.00 to 0.01). We conclude that hyperthermia-free TRPV1 antagonists do not block TRPV1 activation by protons, even if they are potent blockers of the heat mode, and that decreasing the potency to block the capsaicin mode may further decrease the potency to cause hyperthermia.
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Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia
Garami, Andras; Shimansky, Yury P.; Pakai, Eszter; Oliveira, Daniela L.; Gavva, Narender R.; Romanovsky, Andrej A.
2010-01-01
Transient receptor potential vanilloid-1 (TRPV1) antagonists are widely viewed as next-generation pain therapeutics. However, these compounds cause hyperthermia, a serious side effect. TRPV1 antagonists differentially block three modes of TRPV1 activation: by heat, protons, and chemical ligands (e.g., capsaicin). We asked what combination of potencies in these three modes of TRPV1 activation corresponds to the lowest potency of a TRPV1 antagonist to cause hyperthermia. We studied hyperthermic responses of rats, mice, and guinea pigs to eight TRPV1 antagonists with different pharmacological profiles and used mathematical modeling to find a relative contribution of the blockade of each activation mode to the development of hyperthermia. We have found that the hyperthermic effect has the highest sensitivity to the extent of TRPV1 blockade in the proton mode (0.43 to 0.65) with no to moderate sensitivity in the capsaicin mode (-0.01 to 0.34) and no sensitivity in the heat mode (0.00 to 0.01). We conclude that hyperthermia-free TRPV1 antagonists do not block TRPV1 activation by protons, even if they are potent blockers of the heat mode, and that decreasing the potency to block the capsaicin mode may further decrease the potency to cause hyperthermia. PMID:20107070
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Ghobadloo, Shahrokh M.; Balcerzak, Anna K.; Gargaun, Ana; Muharemagic, Darija; Mironov, Gleb G.; Capicciotti, Chantelle J.; Briard, Jennie G.; Ben, Robert N.; Berezovski, Maxim V.
2014-01-01
The inability of vaccines to retain sufficient thermostability has been an obstacle to global vaccination programs. To address this major limitation, we utilized carbohydrate-based ice recrystallization inhibitors (IRIs) to eliminate the cold chain and stabilize the potency of Vaccinia virus (VV), Vesicular Stomatitis virus (VSV) and Herpes virus-1 (HSV-1). The impact of these IRIs was tested on the potency of the viral vectors using a plaque forming unit assay following room temperature storage, cryopreservation with successive freeze-thaw cycles and lyophilization. Viral potency after storage with all three conditions demonstrated that N-octyl-gluconamide (NOGlc) recovered the infectivity of shelf stored VV, 5.6 Log10 PFU mL−1 during 40 days, and HSV-1, 2.7 Log10 PFU mL−1 during 9 days. Carbon-linked antifreeze glycoprotein analogue ornithine-glycine-glycine-galactose (OGG-Gal) increases the recovery of VV and VSV more than 1 Log10 PFU mL−1 after 10 freeze-thaw cycles. In VSV, cryostorage with OGG-Gal maintains high infectivity and reduces temperature-induced aggregation of viral particles by 2 times that of the control. In total, OGG-Gal and NOGlc preserve virus potency during cryostorage. Remarkably, NOGlc has potential to eliminate the cold chain and permit room temperature storage of viral vectors. PMID:25078058
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Murray, Robin M; Quigley, Harriet; Quattrone, Diego; Englund, Amir; Di Forti, Marta
2016-10-01
Epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychotic outcomes, and confirms a dose-response relationship between the level of use and the risk of later psychosis. High-potency cannabis and synthetic cannabinoids carry the greatest risk. Experimental administration of tetrahydrocannabinol, the active ingredient of cannabis, induces transient psychosis in normal subjects, but this effect can be ameliorated by co-administration of cannabidiol. This latter is a constituent of traditional hashish, but is largely absent from modern high-potency forms of cannabis. Argument continues over the extent to which genetic predisposition is correlated to, or interacts with, cannabis use, and what proportion of psychosis could be prevented by minimizing heavy use. As yet, there is not convincing evidence that cannabis use increases risk of other psychiatric disorders, but there are no such doubts concerning its detrimental effect on cognitive function. All of the negative aspects are magnified if use starts in early adolescence. Irrespective of whether use of cannabis is decriminalized or legalized, the evidence that it is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high-potency cannabis and synthetic cannabinoids. © 2016 World Psychiatric Association.
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Aparna, Vasudevan; Dineshkumar, Kesavan; Mohanalakshmi, Narasumani; Velmurugan, Devadasan; Hopper, Waheeta
2014-01-01
Pseudomonas aeruginosa and Escherichia coli are resistant to wide range of antibiotics rendering the treatment of infections very difficult. A main mechanism attributed to the resistance is the function of efflux pumps. MexAB-OprM and AcrAB-TolC are the tripartite efflux pump assemblies, responsible for multidrug resistance in P. aeruginosa and E. coli respectively. Substrates that are more susceptible for efflux are predicted to have a common pharmacophore feature map. In this study, a new criterion of excluding compounds with efflux substrate-like features was used, thereby refining the selection process and enriching the inhibitor identification process. An in-house database of phytochemicals was created and screened using high-throughput virtual screening against AcrB and MexB proteins and filtered by matching with the common pharmacophore models (AADHR, ADHNR, AAHNR, AADHN, AADNR, AAADN, AAADR, AAANR, AAAHN, AAADD and AAADH) generated using known efflux substrates. Phytochemical hits that matched with any one or more of the efflux substrate models were excluded from the study. Hits that do not have features similar to the efflux substrate models were docked using XP docking against the AcrB and MexB proteins. The best hits of the XP docking were validated by checkerboard synergy assay and ethidium bromide accumulation assay for their efflux inhibition potency. Lanatoside C and diadzein were filtered based on the synergistic potential and validated for their efflux inhibition potency using ethidium bromide accumulation study. These compounds exhibited the ability to increase the accumulation of ethidium bromide inside the bacterial cell as evidenced by these increase in fluorescence in the presence of the compounds. With this good correlation between in silico screening and positive efflux inhibitory activity in vitro, the two compounds, lanatoside C and diadzein could be promising efflux pump inhibitors and effective to use in combination therapy against drug resistant strains of P. aeruginosa and E. coli. PMID:25025665
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Aparna, Vasudevan; Dineshkumar, Kesavan; Mohanalakshmi, Narasumani; Velmurugan, Devadasan; Hopper, Waheeta
2014-01-01
Pseudomonas aeruginosa and Escherichia coli are resistant to wide range of antibiotics rendering the treatment of infections very difficult. A main mechanism attributed to the resistance is the function of efflux pumps. MexAB-OprM and AcrAB-TolC are the tripartite efflux pump assemblies, responsible for multidrug resistance in P. aeruginosa and E. coli respectively. Substrates that are more susceptible for efflux are predicted to have a common pharmacophore feature map. In this study, a new criterion of excluding compounds with efflux substrate-like features was used, thereby refining the selection process and enriching the inhibitor identification process. An in-house database of phytochemicals was created and screened using high-throughput virtual screening against AcrB and MexB proteins and filtered by matching with the common pharmacophore models (AADHR, ADHNR, AAHNR, AADHN, AADNR, AAADN, AAADR, AAANR, AAAHN, AAADD and AAADH) generated using known efflux substrates. Phytochemical hits that matched with any one or more of the efflux substrate models were excluded from the study. Hits that do not have features similar to the efflux substrate models were docked using XP docking against the AcrB and MexB proteins. The best hits of the XP docking were validated by checkerboard synergy assay and ethidium bromide accumulation assay for their efflux inhibition potency. Lanatoside C and diadzein were filtered based on the synergistic potential and validated for their efflux inhibition potency using ethidium bromide accumulation study. These compounds exhibited the ability to increase the accumulation of ethidium bromide inside the bacterial cell as evidenced by these increase in fluorescence in the presence of the compounds. With this good correlation between in silico screening and positive efflux inhibitory activity in vitro, the two compounds, lanatoside C and diadzein could be promising efflux pump inhibitors and effective to use in combination therapy against drug resistant strains of P. aeruginosa and E. coli.
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Werb, Dan; Kerr, Thomas; Nosyk, Bohdan; Strathdee, Steffanie; Montaner, Julio; Wood, Evan
2013-09-30
Illegal drug use continues to be a major threat to community health and safety. We used international drug surveillance databases to assess the relationship between multiple long-term estimates of illegal drug price and purity. We systematically searched for longitudinal measures of illegal drug supply indicators to assess the long-term impact of enforcement-based supply reduction interventions. Data from identified illegal drug surveillance systems were analysed using an a priori defined protocol in which we sought to present annual estimates beginning in 1990. Data were then subjected to trend analyses. Data were obtained from government surveillance systems assessing price, purity and/or seizure quantities of illegal drugs; systems with at least 10 years of longitudinal data assessing price, purity/potency or seizures were included. We identified seven regional/international metasurveillance systems with longitudinal measures of price or purity/potency that met eligibility criteria. In the USA, the average inflation-adjusted and purity-adjusted prices of heroin, cocaine and cannabis decreased by 81%, 80% and 86%, respectively, between 1990 and 2007, whereas average purity increased by 60%, 11% and 161%, respectively. Similar trends were observed in Europe, where during the same period the average inflation-adjusted price of opiates and cocaine decreased by 74% and 51%, respectively. In Australia, the average inflation-adjusted price of cocaine decreased 14%, while the inflation-adjusted price of heroin and cannabis both decreased 49% between 2000 and 2010. During this time, seizures of these drugs in major production regions and major domestic markets generally increased. With few exceptions and despite increasing investments in enforcement-based supply reduction efforts aimed at disrupting global drug supply, illegal drug prices have generally decreased while drug purity has generally increased since 1990. These findings suggest that expanding efforts at controlling the global illegal drug market through law enforcement are failing.
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Lu, Xinxing; Han, Hu; Xing, Nianzeng; Tian, Long
2015-09-22
To systematically assess the efficacy and safety of oral sildenafil citrate for post bilateral nerve-sparig radical prostatectomy (post-BNSRP) erectile dysfunction (ED). The following keywords: sildenafil, radical prostatectomy were used to search in Medline, Pubmed, Web of Science, Cochrane Library, CNKI, WanFang Database. The title, abstract and keywords of each article were independently screened by two reviewers. Randomized controlled trials (RCT) published between 1990 and 2014 were retrieved according to our inclusion and exclusion criteria. The efficacy and safety of oral sildenafil citrate for post-BNSRP ED were systematically assessed by meta-analysis. Four RCTs with 320 cases were included after literature retrieval and filtering. The potency rates were 32.1% (35/109) and 11.3% (7/62) between sildenafil and placebo groups after meta-analysis and showed statistically significant differences (OR = 4.66, 95% CI: 1.79-12.11). IIEF-5 score in sildenafil group was significant higher than that in the placebo group (WMD: 4.73, 95% CI: 3.26-6.19). In subgroup meta-analysis, the potency rates in high-dose, low-dose sildenafil groups and placebo groups were 30.4% (14/46), 25.0% (10/40) and 4.5% (2/44), respectively. There were statistically significant differences between the high-dose subgroup and placebo group (OR = 9.32, 95% CI: 1.96-44.23), and the low-dose subgroup and placebo group (OR = 6.99, 95% CI: 1.43-34.22). But there was no significant difference between high-dose and low-dose subgroups (OR = 1.31, 95% CI: 0.51-3.40). Compared with placebo, sildenafil has considerable efficacy for erectile function rehabilitationas as a primary treatment for post-BNSRP ED. There is no significant difference between high-dose and low-dose schedule for its efficacy. However, further studies are required to optimize treatment.
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STABILIZATION OF PERTUSSIS VACCINE IN THE PRESENCE OF BENZETHONIUM CHLORIDE
Olson, B. H.; Eldering, Grace; Graham, Bernice
1964-01-01
Olson, B. H. (Division of Laboratories, Michigan Department of Health, Lansing), Grace Eldering, and Bernice Graham. Stabilization of pertussis vaccine in the presence of benzethonium chloride. J. Bacteriol. 87:543–546. 1964.—Data are presented showing that pertussis vaccine preserved with benzethonium chloride (BC; Phemerol) was inactivated during storage. BC-preserved vaccine stored at 37 C showed no measurable mouse-protective potency at 16 weeks. That stored at 0 to 4 C lost approximately 80% of its potency within 1 year. Treatment of pertussis vaccines with aluminum, calcium, magnesium, choline, or dl-lysine before the addition of the BC prevented its uptake by the cells. Pertussis vaccines pretreated with 0.004 m Ca++ or 0.0004 m Al+++ retained 70% of the initial potency after 42 weeks of storage at 37 C. Similar vaccines showed no loss of protective antigens when stored for 1 year at 0 to 4 C. PMID:14127568
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Lukesh, John C; Carney, Daniel W; Dong, Huijun; Cross, R Matthew; Shukla, Vyom; Duncan, Katharine K; Yang, Shouliang; Brody, Daniel M; Brütsch, Manuela M; Radakovic, Aleksandar; Boger, Dale L
2017-09-14
A series of 180 vinblastine 20' amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure-activity relationships and a structural model were developed in the studies which provided many such 20' amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.
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Kikuchi, Hiroto; Fujisaki, Hiroshi; Furuta, Tadaomi; Okamoto, Ken; Leimkühler, Silke; Nishino, Takeshi
2012-01-01
Febuxostat, a drug recently approved in the US, European Union and Japan for treatment of gout, inhibits xanthine oxidoreductase (XOR)-mediated generation of uric acid during purine catabolism. It inhibits bovine milk XOR with a Ki in the picomolar-order, but we found that it is a much weaker inhibitor of Rhodobacter capsulatus XOR, even though the substrate-binding pockets of mammalian and bacterial XOR are well-conserved as regards to catalytically important residues and three-dimensional structure, and both permit the inhibitor to be accommodated in the active site, as indicated by computational docking studies. To clarify the reason for the difference of inhibitory potency towards the two XORs, we performed molecular dynamics simulations. The results indicate that differences in mobility of hydrophobic residues that do not directly interact with the substrate account for the difference in inhibitory potency. PMID:22448318
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[Effect of 2-phenoxyethanol on potency of Sabin inactivated poliomyelitis vaccine and its safety].
Bian, Chuan-xiu; Jiang, Shu-de; Yang, Jian-yong; Sun, Ming-bo; Xie, Ming-xue; Zhang, Xin-wen; Liao, Guo-yang; Li, Wei-dong
2007-03-01
To investigate the effect of 2-phenoxyethanol on potency of Sabin inactivated poliomyelitis vaccine (IPV). Sabin IPV samples containing 5 mg or 7 mg 2-phenoxyethanol each dosage respectively were placed separately at 4 degrees C, 37 degrees C for 2 days and 7 days. D-antigen contents were tested with ELISA method. Then neutralizing antibodies in mice and guinea pigs were detected. The safety experiment was performed according to unusual toxicity test of China requirement for biological product. After addition of 2-phenoxyethanol, the I, II, and III D-antigen contents of Sabin IPV did not change. The antibody levels in mice and guinea pigs were not different between experimental group and control group. Animals were safe during observation period. 2-Phenoxyethanol had no effect on potency and safety of Sabin IPV. It can be used as antiseptic for Sabin IPV.
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de Lima Toccafondo Vieira, Manuela; Duarte, Rodrigo Ferreira; Campos, Ligia Maria Moreira; Nunan, Elzíria de Aguiar
2008-01-01
Soy phytoestrogens, isoflavones, are a primary class of plant-based estrogen alternatives being sold over the counter nowadays. Genistein, daidzein and glycitein are the major isoflavones found in soybeans, as aglycones and glycosides. Each isoflavone shows distinctive estrogenic activity and pharmacokinetics. Soy dry extracts, employed as pharmaceutical raw material for manufacturing isoflavone supplements, are standardized to contain 40% of total isoflavones, but the amount of each isoflavone is highly diverse. The influence of these compositional differences on the estrogenic potency of soy extracts was evaluated by uterotrophic bioassay. Five commercial samples of standardized soy dry extract, homogeneously suspended in arachis oil, were administered per os in serial doses (125-4150 mg/kg bw/day) to immature female rats for 3 days. Soy extract samples with considerable diversity in isoflavone composition revealed different estrogenic potencies. Our results indicate a need of standardization of the individual isoflavone content in soy extracts.
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Encinas, Lourdes; O'Keefe, Heather; Neu, Margarete; Remuiñán, Modesto J; Patel, Amish M; Guardia, Ana; Davie, Christopher P; Pérez-Macías, Natalia; Yang, Hongfang; Convery, Maire A; Messer, Jeff A; Pérez-Herrán, Esther; Centrella, Paolo A; Alvarez-Gómez, Daniel; Clark, Matthew A; Huss, Sophie; O'Donovan, Gary K; Ortega-Muro, Fátima; McDowell, William; Castañeda, Pablo; Arico-Muendel, Christopher C; Pajk, Stane; Rullás, Joaquín; Angulo-Barturen, Iñigo; Alvarez-Ruíz, Emilio; Mendoza-Losana, Alfonso; Ballell Pages, Lluís; Castro-Pichel, Julia; Evindar, Ghotas
2014-02-27
Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.
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Manosroi, Aranya; Akazawa, Hiroyuki; Pattamapun, Kassara; Kitdamrongtham, Worapong; Akihisa, Toshihiro; Manosroi, Worapaka; Manosroi, Jiradej
2015-07-01
Thai/Lanna medicinal plant recipes have been used for the treatment of several diseases including oral and cervical cancers. To investigate anti-proliferative activity on human cervical (HeLa) and oral (KB) cancer cell lines of medicinal plants selected from Thai/Lanna medicinal plant recipe database "MANOSROI III". Twenty-three methanolic plant crude extracts were tested for phytochemicals and anti-proliferative activity on HeLa and KB cell lines for 24 h by the sulforhodamine B (SRB) assay at the doses of 1 × 10(1)-1 × 10(-6 )mg/ml. The nine extracts with the concentrations giving 50% growth inhibition (GI50) lower than 100 µg/ml were further semi-purified by liquid/liquid partition in order to evaluate and enhance the anti-proliferative potency. All extracts contained steroids/triterpenoids, but not xanthones. The methanolic extracts of Gloriosa superba L. (Colchinaceae) root and Albizia chinensis (Osbeck) Merr. (Leguminosae-Mimosoideae) wood gave the highest anti-proliferative activity on HeLa and KB cell lines with the GI50 values of 0.91 (6.0- and 0.31-fold of cisplatin and doxorubicin) and 0.16 µg/ml (28.78- and 82.29-fold of cisplatin and doxorubicin), respectively. Hexane and methanol-water fractions of G. superba exhibited the highest anti-proliferative activity on HeLa and KB cell lines with the GI50 values of 0.15 (37- and 1.9-fold of cisplatin and doxorubicin) and 0.058 µg/ml (77.45- and 221.46-fold of cisplatin and doxorubicin), respectively. This study has demonstrated the potential of plants selected from MANOSROI III database especially G. superba and A. chinensis for further development as anti-oral and cervical cancer agents.
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Patel, Ami B; Wilds, Brandon W; Deininger, Michael W
2017-07-01
With the discovery of imatinib mesylate nearly 20 years ago, tyrosine kinase inhibitors (TKIs) were found to be effective in chronic myeloid leukemia (CML). TKI therapy has since revolutionized the treatment of CML and has served as a paradigm of success for targeted drug therapy in cancer. Several new TKIs for CML have been approved over the last two decades that exhibit improved potency over imatinib and have different off-target profiles, providing options for individualized therapy selection. Areas covered: Current management of chronic phase CML, including guidance on the sequential use of imatinib and newer-generation TKIs and evolving treatment strategies such as TKI discontinuation. Relevant literature was identified by searching biomedical databases (i.e. PubMed) for primary research material. Expert commentary: Although survival outcomes have drastically improved for CML patients, treatment for CML has grown more complex with the introduction of next-generation TKIs and the advent of treatment-free remissions (TFR). Goals of therapy have shifted accordingly, with increased focus on improving quality of life, managing patient expectations and optimizing patient adherence.
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Emerging antibody-drug conjugates for treating lymphoid malignancies.
Wolska-Washer, Anna; Robak, Pawel; Smolewski, Piotr; Robak, Tadeusz
2017-09-01
Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. These agents should improve the potency of chemotherapy by increasing the accumulation of cytotoxic the drug within or near the neoplastic cells with reduced systemic effects. Areas covered: A literature review was conducted of the MEDLINE database PubMed for articles in English examining Mabs, B-cell receptor pathway inhibitors and immunomodulating drugs. Publications from 2000 through April 2017 were scrutinized. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Expert opinion: Newer ADCs show promise as treatment for several hematologic malignancies, especially lymphoma, multiple myeloma, and leukemia. However, definitive data from ongoing and future clinical trials will aid in better defining the status of these agents in the treatment of these diseases.
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Herbs as an antioxidant arsenal for periodontal diseases
Ramesh, Asha; Varghese, Sheeja Saji; Doraiswamy, Jayakumar Nadathur; Malaiappan, Sankari
2016-01-01
Herbal medicines have long been used as a traditional mode of therapy for various ailments in India. They are being used increasingly as dietary supplements to ward off common diseases. Periodontal diseases are highly prevalent and can affect up to 90% of the world population. Gingivitis is the mild form whereas periodontitis results in an irreversible loss of supporting structures of the teeth. Even though periodontal pathogens form a crucial component in the etiopathogenesis of periodontitis, there is a growing body of evidence suggesting oxidative stress playing a pivotal role in the disease initiation and progression. Studies have shown a direct correlation between increased levels of biomarkers for tissue damage induced by reactive oxygen species (ROS) to the severity of periodontal disease. Thus, the focus of attention has revolved back to herbal medicines due to their wide spectrum of biological and medicinal activities, lower costs, and higher safety margin. Internet databases Pubmed and Google Scholar were searched, and the most relevant articles were considered for review. This review briefly describes the various herbs with antioxidant capacity and their potency in the treating periodontal disease. PMID:27069730
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Antimicrobial Peptides of Meat Origin - An In silico and In vitro Analysis.
Keska, Paulina; Stadnik, Joanna
2017-01-01
The aim of this study was to evaluate the antimicrobial activity of meat protein-derived peptides against selected Gram-positive and Gram-negative bacteria. The in silico and in vitro approach was combined to determine the potency of antimicrobial peptides derived from pig (Sus scrofa) and cow (Bos taurus) proteins. The in silico studies consisted of an analysis of the amino acid composition of peptides obtained from the CAMPR database, their molecular weight and other physicochemical properties (isoelectric point, molar extinction coefficient, instability index, aliphatic index, hydropathy index and net charge). The degree of similarity was estimated between the antimicrobial peptide sequences derived from the slaughtered animals and the main meat proteins. Antimicrobial activity of peptides isolated from dry-cured meat products was analysed (in vitro) against two strains of pathogenic bacteria using the disc diffusion method. There was no evidence of growthinhibitory properties of peptides isolated from dry-cured meat products against Escherichia coli K12 ATCC 10798 and Staphylococcus aureus ATCC 25923. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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Coyne, C P; Jones, Toni; Bear, Ryan
2012-11-01
Immunochemotherapeutics, epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ] with an internal disulfide bond, and epirubicin-(C 3 - amide )-[anti-HER2/ neu ] were synthesized utilizing succinimidyl 2-[(4,4'-azipentanamido) ethyl]-1,3'-dithioproprionate or succinimidyl 4,4-azipentanoate respectively. Western blot analysis was used to determine the presence of any immunoglobulin fragmentation or IgG-IgG polymerization. Retained HER2/ neu binding characteristics of epirubicin-(C 3 - amide )-[anti-HER2/ neu ] and epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ] were validated by cell-ELISA using a mammary adenocarcinoma (SKBr-3) population that highly over-expresses trophic HER2/ neu receptor complexes. Cytotoxic anti-neoplastic potency of epirubicin-(C 3 - amide )-[anti-HER2/ neu ] and epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ] between epirubicin-equivalent concentrations of 10 -10 M and 10 -6 M was determined by measuring the vitality/proliferation of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3 cell type). Cytotoxic anti-neoplastic potency of benzimidazoles (albendazole, flubendazole, membendazole) and griseofulvin were assessed between 0-to-2 μg/ml and 0-to-100 μg/ml respectively while mebendazole and griseofulvin were analyzed at fixed concentrations of 0.35 μg/ml and 35 g/ml respectively in dual combination with gradient concentrations of epirubicin-(C 3 - amide )-[anti-HER2/ neu ] and epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ]. Cytotoxic anti-neoplastic potency for epirubicin-(C 3 - amide )-[anti-HER2/ neu ] and epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ] against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was nearly identical at epirubicin-equivalent concentrations of 10 -10 M and 10 -6 M. The benzimadazoles also possessed cytotoxic anti-neoplastic activity with flubendazole and albendazole being the most and least potent respectively. Similarly, griseofulvin had cytotoxic anti-neoplastic activity and was more potent than methylselenocysteine. Both mebendazole and griseofulvin when applied in dual combination with either epirubicin-(C 3 - amide )-[anti-HER2/ neu ] or epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ] produced enhanced levels of cytotoxic anti-neoplatic potency.
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Martini, Elisabetta; Salvicchi, Alberto; Ghelardini, Carla; Manetti, Dina; Dei, Silvia; Guandalini, Luca; Martelli, Cecilia; Melchiorre, Michele; Cellai, Cristina; Scapecchi, Serena; Teodori, Elisabetta; Romanelli, Maria Novella
2009-11-01
A series of amides and sulfonamides, structurally related to DM235 (sunifiram) and MN19 (sapunifiram), derived by ring expansion or contraction, or by inversion of the exocyclic amide function, have been synthesized and tested for cognition-enhancing activity in the mouse passive-avoidance test. Some of the compounds display good antiamnesic and procognitive activity, with higher potency than piracetam, and with a potency similar to the parent compounds.
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21 CFR 101.54 - Nutrient content claims for “good source,” “high,” “more,” and “high potency.”
Code of Federal Regulations, 2013 CFR
2013-04-01
... 21 Food and Drugs 2 2013-04-01 2013-04-01 false Nutrient content claims for âgood source,â âhigh,â âmore,â and âhigh potency.â 101.54 Section 101.54 Food and Drugs FOOD AND DRUG ADMINISTRATION... Requirements for Nutrient Content Claims § 101.54 Nutrient content claims for “good source,” “high,” “more...
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21 CFR 101.54 - Nutrient content claims for “good source,” “high,” “more,” and “high potency.”
Code of Federal Regulations, 2012 CFR
2012-04-01
... 21 Food and Drugs 2 2012-04-01 2012-04-01 false Nutrient content claims for âgood source,â âhigh,â âmore,â and âhigh potency.â 101.54 Section 101.54 Food and Drugs FOOD AND DRUG ADMINISTRATION... Requirements for Nutrient Content Claims § 101.54 Nutrient content claims for “good source,” “high,” “more...
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21 CFR 101.54 - Nutrient content claims for “good source,” “high,” “more,” and “high potency.”
Code of Federal Regulations, 2014 CFR
2014-04-01
... 21 Food and Drugs 2 2014-04-01 2014-04-01 false Nutrient content claims for âgood source,â âhigh,â âmore,â and âhigh potency.â 101.54 Section 101.54 Food and Drugs FOOD AND DRUG ADMINISTRATION... Requirements for Nutrient Content Claims § 101.54 Nutrient content claims for “good source,” “high,” “more...
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Structure-activity relationship of ortho- and meta-phenol based LFA-1 ICAM inhibitors.
Lin, Edward Yin-Shiang; Guckian, Kevin M; Silvian, Laura; Chin, Donovan; Boriack-Sjodin, P Ann; van Vlijmen, Herman; Friedman, Jessica E; Scott, Daniel M
2008-10-01
LFA-1 ICAM inhibitors based on ortho- and meta-phenol templates were designed and synthesized by Mitsunobu chemistry. The selection of targets was guided by X-ray co-crystal data, and led to compounds which showed an up to 30-fold increase in potency over reference compound 1 in the LFA-1/ICAM1-Ig assay. The most active compound exploited a new hydrogen bond to the I-domain and exhibited subnanomolar potency.
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Dolezal, Rafael; Korabecny, Jan; Malinak, David; Honegr, Jan; Musilek, Kamil; Kuca, Kamil
2015-03-01
To predict unknown reactivation potencies of 12 mono- and bis-pyridinium aldoximes for VX-inhibited rat acetylcholinesterase (rAChE), three-dimensional quantitative structure-activity relationship (3D QSAR) analysis has been carried out. Utilizing molecular interaction fields (MIFs) calculated by molecular mechanical (MMFF94) and quantum chemical (B3LYP/6-31G*) methods, two satisfactory ligand-based CoMFA models have been developed: 1. R(2)=0.9989, Q(LOO)(2)=0.9090, Q(LTO)(2)=0.8921, Q(LMO(20%))(2)=0.8853, R(ext)(2)=0.9259, SDEP(ext)=6.8938; 2. R(2)=0.9962, Q(LOO)(2)=0.9368, Q(LTO)(2)=0.9298, Q(LMO(20%))(2)=0.9248, R(ext)(2)=0.8905, SDEP(ext)=6.6756. High statistical significance of the 3D QSAR models has been achieved through the application of several data noise reduction techniques (i.e. smart region definition SRD, fractional factor design FFD, uninformative/iterative variable elimination UVE/IVE) on the original MIFs. Besides the ligand-based CoMFA models, an alignment molecular set constructed by flexible molecular docking has been also studied. The contour maps as well as the predicted reactivation potencies resulting from 3D QSAR analyses help better understand which structural features are associated with increased reactivation potency of studied compounds. Copyright © 2014 Elsevier Inc. All rights reserved.
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Brevenal is a natural inhibitor of brevetoxin action in sodium channel receptor binding assays.
Bourdelais, Andrea J; Campbell, Susan; Jacocks, Henry; Naar, Jerome; Wright, Jeffery L C; Carsi, Jigani; Baden, Daniel G
2004-08-01
1. Florida red tides produce profound neurotoxicity that is evidenced by massive fish kills, neurotoxic shellfish poisoning, and respiratory distress. Red tides vary in potency, potency that is not totally governed by toxin concentration. The purpose of the study was to understand the variable potency of red tides by evaluating the potential for other natural pharmacological agents which could modulate or otherwise reduce the potency of these lethal environmental events. 2. A synaptosome binding preparation with 3-fold higher specific brevetoxin binding was developed to detect small changes in toxin binding in the presence of potential antagonists. Rodent brain labeled in vitro with tritiated brevetoxin shows high specific binding in the cerebellum as evidenced by autoradiography. Synaptosome binding assays employing cerebellum-derived synaptosomes illustrate 3-fold increased specific binding. 3. A new polyether natural product from Florida's red tide dinoflagellate Karenia brevis, has been isolated and characterized. Brevenal, as the nontoxic natural product is known, competes with tritiated brevetoxin for site 5 associated with the voltage-sensitive sodium channel (VSSC). Brevenal displacement of specific brevetoxin binding is purely competitive in nature. 4. Brevenal, obtained from either laboratory cultures or field collections during a red tide, protects fish from the neurotoxic effects of brevetoxin exposure. 5. Brevenal may serve as a model compound for the development of therapeutics to prevent or reverse intoxication in red tide exposures.
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Knudson, Susan E.; Awasthi, Divya; Kumar, Kunal; Carreau, Alexandra; Goullieux, Laurent; Lagrange, Sophie; Vermet, Hélèn; Ojima, Iwao; Slayden, Richard A.
2014-01-01
Trisubstituted benzimidazoles have demonstrated potency against Gram-positive and Gram-negative bacterial pathogens. Previously, a library of novel trisubstituted benzimidazoles was constructed for high throughput screening, and compounds were identified that exhibited potency against M. tuberculosis H37Rv and clinical isolates, and were not toxic to Vero cells. A new series of 2-cyclohexyl-5-acylamino-6-N, N-dimethylaminobenzimidazoles derivatives has been developed based on SAR studies. Screening identified compounds with potency against M. tuberculosis. A lead compound from this series, SB-P17G-A20, was discovered to have an MIC of 0.16 µg/mL and demonstrated efficacy in the TB murine acute model of infection based on the reduction of bacterial load in the lungs and spleen by 1.73±0.24 Log10 CFU and 2.68±Log10 CFU, respectively, when delivered at 50 mg/kg by intraperitoneal injection (IP) twice daily (bid). The activity of SB-P17G-A20 was determined to be concentration dependent and to have excellent stability in mouse and human plasma, and liver microsomes. Together, these studies demonstrate that SB-P17G-A20 has potency against M. tuberculosis clinical strains with varying susceptibility and efficacy in animal models of infection, and that trisubstituted benzimidazoles continue to be a platform for the development of novel inhibitors with efficacy. PMID:24736743
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Synthesis and biological activity of pyridazine amides, hydrazones and hydrazides.
Buysse, Ann M; Yap, Maurice Ch; Hunter, Ricky; Babcock, Jonathan; Huang, Xinpei
2017-04-01
Optimization studies on compounds initially designed to be herbicides led to the discovery of a series of [6-(3-pyridyl)pyridazin-3-yl]amides exhibiting aphicidal properties. Systematic modifications of the amide moiety as well as the pyridine and pyridazine rings were carried out to determine if these changes could improve insecticidal potency. Structure-activity relationship (SAR) studies showed that changes to the pyridine and pyridazine rings generally resulted in a significant loss of insecticidal potency against green peach aphids [Myzus persicae (Sulzer)] and cotton aphids [(Aphis gossypii (Glover)]. However, replacement of the amide moiety with hydrazines, hydrazones, or hydrazides appeared to be tolerated, with small aliphatic substituents being especially potent. A series of aphicidal [6-(3-pyridyl)pyridazin-3-yl]amides were discovered as a result of random screening of compounds that were intially investigated as herbicides. Follow-up studies of the structure-activity relationship of these [6-(3-pyridyl)pyridazin-3-yl]amides showed that biosteric replacement of the amide moiety was widely tolerated suggesting that further opportunities for exploitation may exist for this new area of insecticidal chemistry. Insecticidal efficacy from the original hit, compound 1, to the efficacy of compound 14 produced greater than 10-fold potency improvement against Aphis gossypii and greater than 14-fold potency improvement against Myzus persicae. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.
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Förster resonance energy transfer competitive displacement assay for human soluble epoxide hydrolase
Lee, Kin Sing Stephen; Morisseau, Christophe; Yang, Jun; Wang, Peng; Hwang, Sung Hee; Hammock, Bruce D.
2013-01-01
The soluble epoxide hydrolase (sEH), responsible for the hydrolysis of various fatty acid epoxides to their corresponding 1,2-diols, is becoming an attractive pharmaceutical target. These fatty acid epoxides, particularly epoxyeicosatrienoic acids (EETs), play an important role in human homeostatic and inflammation processes. Therefore, inhibition of human sEH, which stabilizes EETs in vivo, brings several beneficial effects to human health. Although there are several catalytic assays available to determine the potency of sEH inhibitors, measuring the in vitro inhibition constant (Ki) for these inhibitors using catalytic assay is laborious. In addition, koff, which has been recently suggested to correlate better with the in vivo potency of inhibitors, has never been measured for sEH inhibitors. To better measure the potency of sEH inhibitors, a reporting ligand, 1-(adamantan-1-yl)-3-(1-(2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetyl) piperidin-4-yl)urea (ACPU), was designed and synthesized. With ACPU, we have developed a Förster resonance energy transfer (FRET)-based competitive displacement assay using intrinsic tryptophan fluorescence from sEH. In addition, the resulting assay allows us to measure the Ki values of very potent compounds to the picomolar level and to obtain relative koff values of the inhibitors. This assay provides additional data to evaluate the potency of sEH inhibitors. PMID:23219719
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The preparation and antioxidant activity of glucosamine sulfate
NASA Astrophysics Data System (ADS)
Xing, Ronge; Liu, Song; Wang, Lin; Cai, Shengbao; Yu, Huahua; Feng, Jinhua; Li, Pengcheng
2009-05-01
Glucosamine sulfate was prepared from glucosamine hydrochloride that was produced by acidic hydrolysis of chitin by ion-exchange method. Optical rotation and elemental analysis characterized the degree of its purity. In addition, the antioxidant potency of chitosan derivative-glucosamine sulfate was investigated in various established in vitro systems, such as superoxide (O{2/-})/hydroxyl (·OH) radicals scavenging, reducing power, iron ion chelating. The following results are obtained: first, glucosamine sulfate had pronounced scavenging effect on superoxide radical. For example the O{2/-} scavenging activity of glucosamine sulfate was 92.11% at 0.8 mg/mL. Second, the ·OH scavenging activity of glucosamine sulfate was also strong, and was about 50% at 3.2 mg/mL. Third, the reducing power of glucosamine sulfate was more pronounced. The reducing power of glucosamine sulfate was 0.643 at 0.75 mg/mL. However, its potency for ferrous ion chelating was weak. Furthermore, except for ferrous ion chelating potency, the scavenging rate of radical and reducing power of glucosamine sulfate were concentration-dependent and increased with their increasing concentrations, but its ferrous ion chelating potency decreased with the increasing concentration. The multiple antioxidant activities of glucosamine sulfate were evidents of reducing power and superoxide/hydroxyl radicals scavenging ability. These in vitro results suggest the possibility that glucosamine sulfate could be used effectively as an ingredient in health or functional food, to alleviate oxidative stress.
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Structural Principles in the Development of Cyclic Peptidic Enzyme Inhibitors
Xu, Peng; Andreasen, Peter A.; Huang, Mingdong
2017-01-01
This review summarizes our studies in the development of small cyclic peptides for specifically modulating enzyme activity. Serine proteases share highly similar active sites but perform diverse physiological and pathological functions. From a phage-display peptide library, we isolated two mono-cyclic peptides, upain-1 (CSWRGLENHRMC) and mupain-1 (CPAYSRYLDC), which inhibit the activity of human and murine urokinase-type plasminogen activators (huPA and muPA) with Ki values in the micromolar or sub-micromolar range, respectively. The following affinity maturations significantly enhanced the potencies of the two peptides, 10-fold and >250-fold for upain-1 and mupain-1, respectively. The most potent muPA inhibitor has a potency (Ki = 2 nM) and specificity comparable to mono-clonal antibodies. Furthermore, we also found an unusual feature of mupain-1 that its inhibitory potency can be enhanced by increasing the flexibility, which challenges the traditional viewpoint that higher rigidity leading to higher affinity. Moreover, by changing a few key residues, we converted mupain-1 from a uPA inhibitor to inhibitors of other serine proteases, including plasma kallikrein (PK) and coagulation factor XIa (fXIa). PK and fXIa inhibitors showed Ki values in the low nanomolar range and high specificity. Our studies demonstrate the versatility of small cyclic peptides to engineer inhibitory potency against serine proteases and to provide a new strategy for generating peptide inhibitors of serine proteases. PMID:29104489
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Beech, D. J.; Bolton, T. B.
1989-01-01
1. Single smooth muscle cells were isolated freshly from the rabbit portal vein and membrane currents were recorded by the whole-cell or excised patch configurations of the patch-clamp technique at room temperature. 2. Cromakalim (Ckm, 10 microM) induced a potassium current (ICkm) that showed no pronounced voltage-dependence and had low current noise. 3. This current, ICkm, was inhibited by (in order of potency): phencyclidine greater than quinidine greater than 4-aminopyridine greater than tetraethylammonium ions (TEA). These drugs inhibited the delayed rectifier current, IdK, which is activated by depolarization of the cell, with the same order of potency. 4. Large conductance calcium-activated potassium channels (LKCa) in isolated membrane patches were blocked by (in order of potency) quinidine greater than TEA approximately phencyclidine. 4-Aminopyridine was ineffective. A similar order of potency was found for block of spontaneous transient outward currents thought to represent bursts of openings of LKCa channels. 5. The low current noise of ICkm at positive potentials, and its susceptibility to inhibitors indicated that it was not carried by LKCa channels, and that it may be carried by channels which underlie IdK. It was observed that when ICkm was activated, IdK was reduced. However, in two experiments, ICkm was much more susceptible to glibenclamide than IdK; possible reasons for this are discussed. PMID:2590772
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A study of cannabis potency in France over a 25 years period (1992-2016).
Dujourdy, Laurence; Besacier, Fabrice
2017-03-01
Cannabis contains a unique class of compounds known as the cannabinoids. Pharmacologically, the principal psychoactive constituent is Δ 9 -tetrahydrocannabinol (THC). The amount of THC in conjunction with selected additional cannabinoid compounds (cannabidiol/CBD, cannabinol/CBN), determines the strength or potency of the cannabis product. Recently, reports have speculated over the change in the quality of cannabis products, from nearly a decade, specifically concerning the increase in cannabinoid content. This article exploits the analytical data of cannabis samples analyzed in the five French forensic police laboratories over 25 years. The increase potency of both herbal and resin cannabis in France is proved through the monitoring of THC content. For cannabis resin, it has slowly risen from 1992 to 2009, before a considerable increase in the last four years (mean THC content in mid-2016 is 23% compared to 10% in 2009). For herbal cannabis, it has known three main stages of growth (mean THC content is 13% in 2015 and mid-2016 compared to 7% in 2009 and 2% in 1995). The calculation of THC/CBD ratios in both herbal and resin samples confirms the recent change in chemotypes in favor of high potency categories. Finally, the CBN/THC ratios in marijuana samples were measured in order to evaluate the freshness of French seized hemp. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.
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NASA Astrophysics Data System (ADS)
Burnham, A. D.; Bulanova, G. P.; Smith, C. B.; Whitehead, S. C.; Kohn, S. C.; Gobbo, L.; Walter, M. J.
2016-11-01
Diamonds from the Machado River alluvial deposit have been characterised on the basis of external morphology, internal textures, carbon isotopic composition, nitrogen concentration and aggregation state and mineral inclusion chemistry. Variations in morphology and features of abrasion suggest some diamonds have been derived directly from local kimberlites, whereas others have been through extensive sedimentary recycling. On the basis of mineral inclusion compositions, both lithospheric and sublithospheric diamonds are present at the deposit. The lithospheric diamonds have clear layer-by-layer octahedral and/or cuboid internal growth zonation, contain measurable nitrogen and indicate a heterogeneous lithospheric mantle beneath the region. The sublithospheric diamonds show a lack of regular sharp zonation, do not contain detectable nitrogen, are isotopically heavy (δ13CPDB predominantly - 0.7 to - 5.5) and contain inclusions of ferropericlase, former bridgmanite, majoritic garnet and former CaSiO3-perovskite. This suggests source lithologies that are Mg- and Ca-rich, probably including carbonates and serpentinites, subducted to lower mantle depths. The studied suite of sublithospheric diamonds has many similarities to the alluvial diamonds from Kankan, Guinea, but has more extreme variations in mineral inclusion chemistry. Of all superdeep diamond suites yet discovered, Machado River represents an end-member in terms of either the compositional range of materials being subducted to Transition Zone and lower mantle or the process by which materials are transferred from the subducted slab to the diamond-forming region.
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NASA Astrophysics Data System (ADS)
Sakakibara, M.; Sugawara, H.; Tsuji, T.; Ikehara, M.
2014-05-01
The past two decades have seen the reporting of microbial fossils within ancient oceanic basalts that could be identical to microbes within modern basalts. Here, we present new petrographic, mineralogical, and stable isotopic data for metabasalts containing filamentous structures in a Jurassic accretionary complex within the northern Chichibu Belt of the Yanadani area of central Shikoku, Japan. Mineralized filaments within these rocks are present in interstitial domains filled with calcite, pumpellyite, or quartz, and consist of iron oxide, phengite, and pumpellyite. δ13CPDB values for filament-bearing calcite within these metabasalts vary from -2.49‰ to 0.67‰. A biogenic origin for these filamentous structures is indicated by (1) the geological context of the Yanadani metabasalt, (2) the morphology of the filaments, (3) the carbon isotope composition of carbonates that host the filaments, and (4) the timing of formation of these filaments relative to the timing of low-grade metamorphism in a subduction zone. The putative microorganisms that formed these filaments thrived between eruption (Late Paleozoic) and accretion (Early Jurassic) of the basalt. The data presented here indicate that cryptoendolithic life was present within water-filled vesicles in pre-Jurassic intraplate basalts. The mineralogy of the filaments reflects the low-grade metamorphic recrystallization of authigenic microbial clays similar to those formed by the encrustation of prokaryotes in modern iron-rich environments. These findings suggest that a previously unusual niche for life is present within intraplate volcanic rocks in accretionary complexes.
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In vivo potency revisited - Keep the target in sight.
Gabrielsson, Johan; Peletier, Lambertus A; Hjorth, Stephan
2018-04-01
Potency is a central parameter in pharmacological and biochemical sciences, as well as in drug discovery and development endeavors. It is however typically defined in terms only of ligand to target binding affinity also in in vivo experimentation, thus in a manner analogous to in in vitro studies. As in vivo potency is in fact a conglomerate of events involving ligand, target, and target-ligand complex processes, overlooking some of the fundamental differences between in vivo and in vitro may result in serious mispredictions of in vivo efficacious dose and exposure. The analysis presented in this paper compares potency measures derived from three model situations. Model A represents the closed in vitro system, defining target binding of a ligand when total target and ligand concentrations remain static and constant. Model B describes an open in vivo system with ligand input and clearance (Cl (L) ), adding in parallel to the turnover (k syn , k deg ) of the target. Model C further adds to the open in vivo system in Model B also the elimination of the target-ligand complex (k e(RL) ) via a first-order process. We formulate corresponding equations of the equilibrium (steady-state) relationships between target and ligand, and complex and ligand for each of the three model systems and graphically illustrate the resulting simulations. These equilibrium relationships demonstrate the relative impact of target and target-ligand complex turnover, and are easier to interpret than the more commonly used ligand-, target- and complex concentration-time courses. A new potency expression, labeled L 50 , is then derived. L 50 is the ligand concentration at half-maximal target and complex concentrations and is an amalgamation of target turnover, target-ligand binding and complex elimination parameters estimated from concentration-time data. L 50 is then compared to the dissociation constant K d (target-ligand binding affinity), the conventional Black & Leff potency estimate EC 50 , and the derived Michaelis-Menten parameter K m (target-ligand binding and complex removal) across a set of literature data. It is evident from a comparison between parameters derived from in vitro vs. in vivo experiments that L 50 can be either numerically greater or smaller than the K d (or K m ) parameter, primarily depending on the ratio of k deg -to-k e(RL) . Contrasting the limit values of target R and target-ligand complex RL for ligand concentrations approaching infinity demonstrates that the outcome of the three models differs to a great extent. Based on the analysis we propose that a better understanding of in vivo pharmacological potency requires simultaneous assessment of the impact of its underlying determinants in the open system setting. We propose that L 50 will be a useful parameter guiding predictions of the effective concentration range, for translational purposes, and assessment of in vivo target occupancy/suppression by ligand, since it also encompasses target turnover - in turn also subject to influence by pathophysiology and drug treatment. Different compounds may have similar binding affinity for a target in vitro (same K d ), but vastly different potencies in vivo. L 50 points to what parameters need to be taken into account, and particularly that closed-system (in vitro) parameters should not be first choice when ranking compounds in vivo (open system). Copyright © 2017 Elsevier Inc. All rights reserved.
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Plasma metabolomic profiles of breast cancer patients after short-term limonene intervention.
Miller, Jessica A; Pappan, Kirk; Thompson, Patricia A; Want, Elizabeth J; Siskos, Alexandros P; Keun, Hector C; Wulff, Jacob; Hu, Chengcheng; Lang, Julie E; Chow, H-H Sherry
2015-01-01
Limonene is a lipophilic monoterpene found in high levels in citrus peel. Limonene demonstrates anticancer properties in preclinical models with effects on multiple cellular targets at varying potency. While of interest as a cancer chemopreventive, the biologic activity of limonene in humans is poorly understood. We conducted metabolite profiling in 39 paired (pre/postintervention) plasma samples from early-stage breast cancer patients receiving limonene treatment (2 g QD) before surgical resection of their tumor. Metabolite profiling was conducted using ultra-performance liquid chromatography coupled to a linear trap quadrupole system and gas chromatography-mass spectrometry. Metabolites were identified by comparison of ion features in samples to a standard reference library. Pathway-based interpretation was conducted using the human metabolome database and the MetaCyc database. Of the 397 named metabolites identified, 72 changed significantly with limonene intervention. Class-based changes included significant decreases in adrenal steroids (P < 0.01), and significant increases in bile acids (P ≤ 0.05) and multiple collagen breakdown products (P < 0.001). The pattern of changes also suggested alterations in glucose metabolism. There were 47 metabolites whose change with intervention was significantly correlated to a decrease in cyclin D1, a cell-cycle regulatory protein, in patient tumor tissues (P ≤ 0.05). Here, oral administration of limonene resulted in significant changes in several metabolic pathways. Furthermore, pathway-based changes were related to the change in tissue level cyclin D1 expression. Future controlled clinical trials with limonene are necessary to determine the potential role and mechanisms of limonene in the breast cancer prevention setting. ©2014 American Association for Cancer Research.
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Cholecystokinin receptors on gallbladder muscle and pancreatic acinar cells: a comparative study
DOE Office of Scientific and Technical Information (OSTI.GOV)
von Schrenck, T.; Moran, T.H.; Heinz-Erian, P.
1988-10-01
To compare receptors for cholecystokinin (CCK) in pancreas and gallbladder, we measured binding of 125I-Bolton-Hunter-labeled CCK-8 (125I-BH-CCK-8) to tissue sections from guinea pig gallbladder and pancreas under identical conditions. In both tissues, binding had similar time-, temperature-, and pH dependence, was reversible, saturable and inhibited only by CCK related peptides or CCK receptor antagonists. Autoradiography localized 125I-BH-CCK-8 binding to the smooth muscle layer in the gallbladder. Binding of 125I-BH-CCK-8 to gallbladder sections was inhibited by various agonists with the following potencies (IC50):CCK-8 (0.4 nM) greater than des(SO3)CCK-8 (0.07 microM) greater than gastrin-17-I (1.7 +/- 0.3 microM) and by various receptormore » antagonists with the following potencies: L364,718 (1.5 nM) greater than CR 1409 (0.19 microM) greater than asperlicin = CBZ-CCK-(27-32)-NH2 (1 microM) greater than Bt2cGMP (120 microM). Similar potencies were found for the agonists and antagonists for pancreas sections. Inhibition of binding of 125I-BH-CCK-8 by 11 different analogues of proglumide gave similar potencies for both pancreas and gallbladder. The potencies of agonists in stimulating and antagonists in inhibiting CCK-stimulated contraction or amylase release correlated closely with their abilities to inhibit 125I-BH-CCK-8 binding to gallbladder or pancreas sections or acini, respectively. The present results demonstrate and characterize a method that can be used to compare the CCK receptors in guinea pig gallbladder and pancreas under identical conditions. Moreover, this study demonstrates that gallbladder and pancreatic CCK receptors have similar affinities for the various agonists and antagonists tested and, therefore, provides no evidence that they represent different subtypes of CCK receptors that can be distinguished pharmacologically.« less
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Stress Induces AMP-Dependent Loss of Potency Factors Id2 and Cdx2 in Early Embryos and Stem Cells
Xie, Yufen; Awonuga, Awoniyi; Liu, Jian; Rings, Edmond; Puscheck, Elizabeth Ella
2013-01-01
The AMP-activated protein kinase (AMPK) mediates rapid, stress-induced loss of the inhibitor of differentiation (Id)2 in blastocysts and trophoblast stem cells (TSC), and a lasting differentiation in TSC. However, it is not known if AMPK regulates other potency factors or regulates them before the blastocyst stage. The caudal-related homeodomain protein (Cdx)2 is a regulatory gene for determining TSC, the earliest placental lineage in the preimplantation mouse embryo, but is expressed in the oocyte and in early cleavage stage embryos before TSC arise. We assayed the expression of putative potency-maintaining phosphorylated Cdx2 ser60 in the oocyte, two-cell stage embryo, blastocyst, and in TSC. We studied the loss of Cdx2 phospho ser60 expression induced by hyperosmolar stress and its underlying mechanisms. Hyperosmolar stress caused rapid loss of nuclear Cdx2 phospho ser60 and Id2 in the two-cell stage embryo by 0.5 h. Stress-induced Cdx2 phospho ser60 and Id2 loss is reversed by the AMPK inhibitor compound C and is induced by the AMPK agonist 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide in the absence of stress. In the two-cell stage embryo and TSC hyperosmolar, stress caused AMPK-mediated loss of Cdx2 phospho ser60 as detected by immunofluorescence and immunoblot. We propose that AMPK may be the master regulatory enzyme for mediating stress-induced loss of potency as AMPK is also required for stress-induced loss of Id2 in blastocysts and TSC. Since AMPK mediates potency loss in embryos and stem cells it will be important to measure, test mechanisms for, and manage the AMPK function to optimize the stem cell and embryo quality in vitro and in vivo. PMID:23316940
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Bell, Iris R; Brooks, Audrey J; Howerter, Amy; Jackson, Nicholas; Schwartz, Gary E
2011-10-01
Homeopathic pathogenetic trials usually rely on symptom self report measures. Adding objective biomarkers could enhance detection of subtle initial remedy effects. The present feasibility study examined electroencephalographic (EEG) effects of repeated olfactory administration of two polycrest remedies. College student volunteers (ages 18-30, both sexes) from an introductory psychology course were screened for good health and relatively elevated Sulphur or Pulsatilla symptom scores on the Homeopathic Constitutional Type Questionnaire (CTQ). Subjects underwent a series of 3 once-weekly double-blind sessions during which they repeatedly sniffed the remedy matched to their CTQ type and solvent controls. Each remedy was given in a 6c, 12c, and 30c potency, one potency per week, in randomly assigned order. Solvent controls included both plain distilled water and a water-ethanol (95%) solution. All sniff test solutions were further diluted just prior to laboratory sessions (0.5 ml test solution in 150 ml distilled water). Within a session, remedies and control solvents were administered via 2-s sniffs (8 sniffs of each of 4 different succussion levels for the potency in randomized order). Primary outcome variable was relative EEG power (alpha 1 8-10 Hz; alpha 2 10-12 Hz) averaged over 19 electrode sites, including all succussions for a given potency. Mixed-effect models revealed significant main effects for remedy type (Sulphur >Pulsatilla) in both alpha bands, controlling for gender, baseline resting EEG alpha, and solvent control responses. Additional analyses showed significant nonlinear interactions between dilution and time (weekly session) in alpha 2 for both remedies and alpha 1 for Sulphur. EEG alpha offers an objective biomarker of remedy effects for future studies and potential method for distinguishing time-dependent effects of specific remedies and remedy potencies from one another. Copyright © 2011 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.
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Bell, Iris R.; Brooks, Audrey J.; Howerter, Amy; Jackson, Nicholas; Schwartz, Gary E.
2011-01-01
Introduction Homeopathic pathogenetic trials usually rely on symptom self report measures. Adding objective biomarkers could enhance detection of subtle initial remedy effects. The present feasibility study examined electroencephalographic (EEG) effects of repeated olfactory administration of two polycrest remedies. Methods College student volunteers (ages 18–30, both sexes) from an introductory psychology course were screened for good health and relatively elevated Sulphur OR Pulsatilla symptom scores on the Homeopathic Constitutional Type Questionnaire. Subjects underwent a series of 3 once-weekly double-blind sessions during which they repeatedly sniffed the remedy matched to their CTQ type and solvent controls. Each remedy was given in a 6c, 12c, and 30c potency, one potency per week, in randomly assigned order. Solvent controls included both plain distilled water and a water-ethanol (95%) solution. All sniff test solutions were further diluted just prior to laboratory sessions (0.5 ml test solution in 150 ml distilled water). Within a session, remedies and control solvents were administered via 2-second sniffs (8 sniffs of each of 4 different succussion levels for the potency in randomized order). Primary outcome variable was relative EEG power (alpha 1 8–10 hertz; alpha 2 10–12 hertz) averaged over 19 electrode sites, including all succussions for a given potency. Results Mixed-effect models revealed significant main effects for remedy type (Sulphur>Pulsatilla) in both alpha bands, controlling for gender, baseline resting EEG alpha, and solvent control responses. Additional analyses showed significant non-linear interactions between dilution and time (weekly session) in alpha 2 for both remedies and alpha 1 for Sulphur. Conclusion EEG alpha offers an objective biomarker of remedy effects for future studies and potential method for distinguishing time-dependent effects of specific remedies and remedy potencies from one another. PMID:21962194
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Progress in applying the Three Rs to the potency testing of Botulinum toxin type A.
Straughan, Donald
2006-06-01
Botulinum toxin type A (BTA) is being increasingly used for a range of therapeutic purposes and also for cosmetic reasons. For many years, the potency of BTA has been measured by using an LD50 assay in mice. This assay is a cause for concern due to its unpleasant nature and extreme severity, and the requirement for high numbers of mice to be used. Alternatives to this potency assay are presently reviewed with particular reference to the work at the National Institute for Biological Standards and Control (NIBSC), and to recent work by the UK manufacturer of the substance. An in vivo local paralysis assay with considerably less severity has been developed and is in use at the NIBSC. Alternative, ex vivo functional assays in use include the measurement of BTA-induced paralysis of neurally-stimulated rodent diaphragm or rat intercostal muscle. The latter method has the advantage of allowing more preparations to be derived from one animal. However, these ex vivo methods have not yet been fully validated and accepted by regulatory agencies as potency assays. Endopeptidase assays, although not measuring muscle paralysis directly, may provide a very useful consistency test for batch release and may replace the routine use of the LD50 test for that purpose. These assays measure the cleavage of the SNAP-25 protein (the final stage of BTA action), and have been validated for batch release by the National Control Laboratory (NIBSC), and are in regular use there. ELISA assays, used alongside the endopeptidase assay, also provide useful confirmatory information on the amounts of functional (and non-functional) BTA present. The UK manufacturer is further validating its endopeptidase assay, an ex vivo muscle assay and an ELISA. It is anticipated that their work will lead to a change in the product license, hopefully within the next two years, and will form a critical milestone towards the end of the LD50 potency test.
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Dinunzio, James C; Brough, Chris; Hughey, Justin R; Miller, Dave A; Williams, Robert O; McGinity, James W
2010-02-01
Many techniques for the production of solid dispersions rely on elevated temperatures and prolonged material residence times, which can result in decomposition of temperature-sensitive components. In this study, hydrocortisone was used as a model temperature-sensitive active ingredient to study the effect of formulation and processing techniques as well as to characterize the benefits of KinetiSol Dispersing for the production of solid dispersions. Preformulation studies were conducted using differential scanning calorimetry and hot stage microscopy to identify optimum carriers for the production of amorphous solid dispersions. After identification, solid dispersions were prepared by hot melt extrusion and KinetiSol Dispersing, with material characterized by X-ray diffraction, dissolution and potency testing to evaluate physicochemical properties. Results from the preformulation studies showed that vinylacetate:vinylpyrrolidone (PVPVA) copolymer allowed for hydrocortisone dissolution within the carrier at temperatures as low as 160 degrees C, while hydroxypropyl methylcellulose required temperatures upward of 180 degrees C to facilitate solubilization. Low substituted hydroxypropyl cellulose, a high glass transition temperature control, showed that the material was unable to solubilize hydrocortisone. Manufacturing process control studies using hot melt extruded compositions of hydrocortisone and PVPVA showed that increased temperatures and residence times negatively impacted product potency due to decomposition. Using KinetiSol Dispersing to reduce residence time and to facilitate lower temperature processing, it was possible to produce solid dispersions with improved product potency. This study clearly demonstrated the importance of carrier selection to facilitate lower temperature processing, as well as the effect of residence time on product potency. Furthermore, KinetiSol Dispersing provided significant advantages over hot melt extrusion due to the reduced residence times and lower required processing temperatures. This allowed for the production of solid dispersions with enhanced product potency. Copyright (c) 2009 Elsevier B.V. All rights reserved.
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Turner, Richard M; Yin, Peng; Hanson, Anita; FitzGerald, Richard; Morris, Andrew P; Stables, Rod H; Jorgensen, Andrea L; Pirmohamed, Munir
High-potency statin therapy is recommended in the secondary prevention of cardiovascular disease but discontinuation, dose reduction, statin switching, and/or nonadherence occur in practice. To determine the prevalence and predictors of deviation from high-potency statin use early after a non-ST elevation acute coronary syndrome (NSTE-ACS) and its association with subsequent major adverse cardiovascular events (MACE) and all-cause mortality (ACM). A total of 1005 patients from a UK-based prospective NSTE-ACS cohort study discharged on high-potency statin therapy (atorvastatin 80 mg, rosuvastatin 20 mg, or 40 mg daily) were included. At 1 month, patients were divided into constant high-potency statin users, and suboptimal users incorporating statin discontinuation, dose reduction, switching statin to a lower equivalent potency, and/or statin nonadherence. Follow-up was a median of 16 months. There were 156 suboptimal (∼15.5%) and 849 constant statin users. Factors associated in multivariable analysis with suboptimal statin occurrence included female sex (odds ratio 1.75, 95% confidence interval [CI] 1.14-2.68) and muscular symptoms (odds ratio 4.28, 95% CI 1.30-14.08). Suboptimal statin use was associated with increased adjusted risks of time to MACE (hazard ratio 2.10, 95% CI 1.25-3.53, P = .005) and ACM (hazard ratio 2.46, 95% CI 1.38-4.39, P = .003). Subgroup analysis confirmed that the increased MACE/ACM risks were principally attributable to statin discontinuation or nonadherence. Conversion to suboptimal statin use is common early after NSTE-ACS and is partly related to muscular symptoms. Statin discontinuation or non-adherence carries an adverse prognosis. Interventions that preserve and enhance statin utilization could improve post NSTE-ACS outcomes. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.
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McCoull, William; Addie, Matthew S; Birch, Alan M; Birtles, Susan; Buckett, Linda K; Butlin, Roger J; Bowker, Suzanne S; Boyd, Scott; Chapman, Stephen; Davies, Robert D M; Donald, Craig S; Green, Clive P; Jenner, Chloe; Kemmitt, Paul D; Leach, Andrew G; Moody, Graeme C; Gutierrez, Pablo Morentin; Newcombe, Nicholas J; Nowak, Thorsten; Packer, Martin J; Plowright, Alleyn T; Revill, John; Schofield, Paul; Sheldon, Chris; Stokes, Steve; Turnbull, Andrew V; Wang, Steven J Y; Whalley, David P; Wood, J Matthew
2012-06-15
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship. Copyright © 2012 Elsevier Ltd. All rights reserved.
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Synthesis and Agonistic Activity at the GPR35 of 5,6-Dihydroxyindole-2-carboxylic Acid Analogues
2012-01-01
5,6-Dihydroxyindole-2-carboxylic acid (DHICA), an intermediate of melanin synthesis and an eumelanin building block, was recently discovered to be a GPR35 agonist with moderate potency. Here, we report the synthesis and pharmacological characterization of a series of DHICA analogues against GPR35 using both label-free dynamic mass redistribution and Tango β-arrestin translocation assays. This led to identification of novel GPR35 agonists with improved potency and/or having biased agonism. PMID:24900508
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High-pressure liquid chromatography analysis of antibiotic susceptibility disks.
Hagel, R B; Waysek, E H; Cort, W M
1979-01-01
The analysis of antibiotic susceptibility disks by high-pressure liquid chromatography (HPLC) was investigated. Methods are presented for the potency determination of mecillinam, ampicillin, carbenicillin, and cephalothin alone and in various combinations. Good agreement between HPLC and microbiological data is observed for potency determinations with recoveries of greater than 95%. Relative standard deviations of lower than 2% are recorded for each HPLC method. HPLC methods offer improved accuracy and greater precision when compared to the standard microbiological methods of analysis for susceptibility disks. PMID:507793
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De Los Angeles, Alejandro; Ferrari, Francesco; Xi, Ruibin; Fujiwara, Yuko; Benvenisty, Nissim; Deng, Hongkui; Hochedlinger, Konrad; Jaenisch, Rudolf; Lee, Soohyun; Leitch, Harry G; Lensch, M William; Lujan, Ernesto; Pei, Duanqing; Rossant, Janet; Wernig, Marius; Park, Peter J; Daley, George Q
2015-09-24
Stem cells self-renew and generate specialized progeny through differentiation, but vary in the range of cells and tissues they generate, a property called developmental potency. Pluripotent stem cells produce all cells of an organism, while multipotent or unipotent stem cells regenerate only specific lineages or tissues. Defining stem-cell potency relies upon functional assays and diagnostic transcriptional, epigenetic and metabolic states. Here we describe functional and molecular hallmarks of pluripotent stem cells, propose a checklist for their evaluation, and illustrate how forensic genomics can validate their provenance.
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Zhao, Min; Zheng, Zi-Zheng; Chen, Man; Modjarrad, Kayvon; Zhang, Wei; Zhan, Lu-Ting; Cao, Jian-Li; Sun, Yong-Peng; McLellan, Jason S; Graham, Barney S; Xia, Ning-Shao
2017-08-01
Palivizumab, a humanized murine monoclonal antibody that recognizes antigenic site II on both the prefusion (pre-F) and postfusion (post-F) conformations of the respiratory syncytial virus (RSV) F glycoprotein, is the only prophylactic agent approved for use for the treatment of RSV infection. However, its relatively low neutralizing potency and high cost have limited its use to a restricted population of infants at high risk of severe disease. Previously, we isolated a high-potency neutralizing antibody, 5C4, that specifically recognizes antigenic site Ø at the apex of the pre-F protein trimer. We compared in vitro and in vivo the potency and protective efficacy of 5C4 and the murine precursor of palivizumab, antibody 1129. Both antibodies were synthesized on identical murine backbones as either an IgG1 or IgG2a subclass and evaluated for binding to multiple F protein conformations, in vitro inhibition of RSV infection and propagation, and protective efficacy in mice. Although 1129 and 5C4 had similar pre-F protein binding affinities, the 5C4 neutralizing activity was nearly 50-fold greater than that of 1129 in vitro In BALB/c mice, 5C4 reduced the peak titers of RSV 1,000-fold more than 1129 did in both the upper and lower respiratory tracts. These data indicate that antibodies specific for antigenic site Ø are more efficacious at preventing RSV infection than antibodies specific for antigenic site II. Our data also suggest that site Ø-specific antibodies may be useful for the prevention or treatment of RSV infection and support the use of the pre-F protein as a vaccine antigen. IMPORTANCE There is no vaccine yet available to prevent RSV infection. The use of the licensed antibody palivizumab, which recognizes site II on both the pre-F and post-F proteins, is restricted to prophylaxis in neonates at high risk of severe RSV disease. Recommendations for using passive immunization in the general population or for therapy in immunocompromised persons with persistent infection is limited because of cost, determined from the high doses needed to compensate for its relatively low neutralizing potency. Prior efforts to improve the in vitro potency of site II-specific antibodies did not translate to significant in vivo dose sparing. We isolated a pre-F protein-specific, high-potency neutralizing antibody (5C4) that recognizes antigenic site Ø and compared its efficacy to that of the murine precursor of palivizumab (antibody 1129) matched for isotype and pre-F protein binding affinities. Our findings demonstrate that epitope specificity is an important determinant of antibody neutralizing potency, and defining the mechanisms of neutralization has the potential to identify improved products for the prevention and treatment of RSV infection. Copyright © 2017 American Society for Microbiology.
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2016-01-01
A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug–drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor. PMID:27997172
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Stummann, Tina C; Salvati, Patricia; Fariello, Ruggero G; Faravelli, Laura
2005-03-14
Tetrodotoxin-resistant and tetrodotoxin-sensitive Na+ channels contribute to the abnormal spontaneous firing in dorsal root ganglion neurons associated with neuropathic pain. Effects of the anti-nociceptive agent ralfinamide on tetrodotoxin-resistant and tetrodotoxin-sensitive currents in rat dorsal root ganglion neurons were therefore investigated by patch clamp experiments. Ralfinamide inhibition was voltage-dependent showing highest potency towards inactivated channels. IC50 values for tonic block of half-maximal inactivated tetrodotoxin-resistant and tetrodotoxin-sensitive currents were 10 microM and 22 microM. Carbamazepine, an anticonvulsant used in the treatment of pain, showed significantly lower potency. Ralfinamide produced a hyperpolarising shift in the steady-state inactivation curves of both currents confirming the preferential interaction with inactivated channels. Additionally, ralfinamide use and frequency dependently inhibited both currents and significantly delayed repriming from inactivation. All effects were more pronounced for tetrodotoxin-resistant than tetrodotoxin-sensitive currents. The potency and mechanisms of actions of ralfinamide provide a hypothesis for the anti-nociceptive properties found in animal models.
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International collaborative studies on potency assays of diphtheria and tetanus toxoids.
Van Ramshorst, J D; Sundaresan, T K; Outschoorn, A S
1972-01-01
Collaborative studies showed that relative potency assays for a particular type of diphtheria toxoid (adsorbed) and for tetanus toxoid (plain and adsorbed) gave very similar results, whether the assays were carried out by toxin challenge or by antitoxin titration after immunization of experimental animals with graded doses of toxoid. The same numerical results were obtained with a scoring system as with a system based on survivals only. Although skin tests were used on a very limited scale in these studies, it seems likely that they could replace lethal tests for the diphtheria challenge assays.For both tetanus and diphtheria, the adsorbed toxoid gave a higher relative potency when combined with other antigens than as a single toxoid. Both mice and guinea-pigs were used for the lethal challenge test of adsorbed tetanus toxoid. For the single tetanus toxoid the results were the same, but for the combined toxoid (DPT vaccine) the mouse assay results were about twice those of guinea-pig assays.
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International collaborative studies on potency assays of diphtheria and tetanus toxoids
van Ramshorst, J. D.; Sundaresan, T. K.; Outschoorn, A. S.
1972-01-01
Collaborative studies showed that relative potency assays for a particular type of diphtheria toxoid (adsorbed) and for tetanus toxoid (plain and adsorbed) gave very similar results, whether the assays were carried out by toxin challenge or by antitoxin titration after immunization of experimental animals with graded doses of toxoid. The same numerical results were obtained with a scoring system as with a system based on survivals only. Although skin tests were used on a very limited scale in these studies, it seems likely that they could replace lethal tests for the diphtheria challenge assays. For both tetanus and diphtheria, the adsorbed toxoid gave a higher relative potency when combined with other antigens than as a single toxoid. Both mice and guinea-pigs were used for the lethal challenge test of adsorbed tetanus toxoid. For the single tetanus toxoid the results were the same, but for the combined toxoid (DPT vaccine) the mouse assay results were about twice those of guinea-pig assays. PMID:4537488
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Liu, Junbo; Ma, Jun
2014-01-01
The Drosophila morphogen gradient of Bicoid (Bcd) initiates anterior-posterior (AP) patterning, but it is poorly understood how its ability to activate a target gene may impact this process. Here we report an F-box protein, Dampened (Dmpd) as a nuclear co-factor of Bcd that can enhance its activating potency. We establish a quantitative platform to specifically investigate two parameters of a Bcd target gene response, expression amplitude and boundary position. We show that embryos lacking Dmpd have a reduced amplitude of Bcd-activated hunchback (hb) expression at a critical time of development. This is due to a reduced Bcd-dependent transcribing probability. This defect is faithfully propagated further downstream of the AP patterning network to alter the spatial characteristics of even-skipped (eve) stripes. Thus, unlike another Bcd-interacting F-box protein Fates-shifted (Fsd), which controls AP patterning through regulating the Bcd gradient profile, Dmpd achieves its patterning role through regulating the activating potency of Bcd. PMID:24336107
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Vickers, Timothy A.; Freier, Susan M.; Bui, Huynh-Hoa; Watt, Andrew; Crooke, Stanley T.
2014-01-01
A new strategy for identifying potent RNase H-dependent antisense oligonucleotides (ASOs) is presented. Our analysis of the human transcriptome revealed that a significant proportion of genes contain unique repeated sequences of 16 or more nucleotides in length. Activities of ASOs targeting these repeated sites in several representative genes were compared to those of ASOs targeting unique single sites in the same transcript. Antisense activity at repeated sites was also evaluated in a highly controlled minigene system. Targeting both native and minigene repeat sites resulted in significant increases in potency as compared to targeting of non-repeated sites. The increased potency at these sites is a result of increased frequency of ASO/RNA interactions which, in turn, increases the probability of a productive interaction between the ASO/RNA heteroduplex and human RNase H1 in the cell. These results suggest a new, highly efficient strategy for rapid identification of highly potent ASOs. PMID:25334092
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Molenaar, Ger; de Waard, Vivian; Lutgens, Esther; van Eck-Smit, Berthe L. F.; de Bruin, Kora; Piek, Jan J.; Eersels, Jos L. H.; Booij, Jan; Verberne, Hein J.; Windhorst, Albert D.
2017-01-01
Molecular imaging of matrix metalloproteinases (MMPs) may allow detection of atherosclerotic lesions vulnerable to rupture. In this study, we develop a novel radiolabelled compound that can target gelatinase MMP subtypes (MMP2/9) with high selectivity and inhibitory potency. Inhibitory potencies of several halogenated analogues of MMP subtype-selective inhibitors (N-benzenesulfonyliminodiacetyl monohydroxamates and N-halophenoxy-benzenesulfonyl iminodiacetyl monohydroxamates) were in the nanomolar range for MMP2/9. The analogue with highest inhibitory potency and selectivity was radiolabelled with [123I], resulting in moderate radiochemical yield, and high radiochemical purity. Biodistribution studies in mice, revealed stabilization in blood 1 hour after intravenous bolus injection. Intravenous infusion of the radioligand and subsequent autoradiography of excised aortas showed tracer uptake in atheroprone mice. Distribution of the radioligand showed co-localization with MMP2/9 immunohistochemical staining. In conclusion, we have developed a novel selective radiolabeled MMP2/9 inhibitor, suitable for single photon emission computed tomography (SPECT) imaging that effectively targets atherosclerotic lesions in mice. PMID:29190653
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Glucose-responsive insulin by molecular and physical design
NASA Astrophysics Data System (ADS)
Bakh, Naveed A.; Cortinas, Abel B.; Weiss, Michael A.; Langer, Robert S.; Anderson, Daniel G.; Gu, Zhen; Dutta, Sanjoy; Strano, Michael S.
2017-10-01
The concept of a glucose-responsive insulin (GRI) has been a recent objective of diabetes technology. The idea behind the GRI is to create a therapeutic that modulates its potency, concentration or dosing relative to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. From the perspective of the medicinal chemist, the GRI is also important as a generalized model of a potentially new generation of therapeutics that adjust potency in response to a critical therapeutic marker. The aim of this Perspective is to highlight emerging concepts, including mathematical modelling and the molecular engineering of insulin itself and its potency, towards a viable GRI. We briefly outline some of the most important recent progress toward this goal and also provide a forward-looking viewpoint, which asks if there are new approaches that could spur innovation in this area as well as to encourage synthetic chemists and chemical engineers to address the challenges and promises offered by this therapeutic approach.
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Ho, C L; Li, C H
1985-03-01
Three synthetic analogs of human beta-endorphin (beta h-EP) (I, [Gln8, Gly31]-beta h-EP-Gly-Gly-NH2; II, [Arg9,12,24,28,29]-beta h-EP and III, [Cys11,26, Phe27, Gly31]-beta h-EP), which have been shown to possess potent inhibiting activity to beta h-EP-induced analgesia, were assayed in rat vas deferens and guinea pig ileum bioassay systems. In the rat vas deferens assay, relative potencies of these analogs were beta h-EP, 100; I, 30; II, 40; III, 1, whereas in the guinea pig ileum assay: beta h-EP, 100; I, 184; II, 81; III, 163. From previous studies on their analgesia potency in mice and opiate receptor-binding activity in rat brain membranes, their activity in rat vas deferens correlates well with the analgesic potency and the activity from guinea pig ileum assay shows good correlations with that from the opiate receptor-binding assay.
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Glucose-responsive insulin by molecular and physical design.
Bakh, Naveed A; Cortinas, Abel B; Weiss, Michael A; Langer, Robert S; Anderson, Daniel G; Gu, Zhen; Dutta, Sanjoy; Strano, Michael S
2017-09-22
The concept of a glucose-responsive insulin (GRI) has been a recent objective of diabetes technology. The idea behind the GRI is to create a therapeutic that modulates its potency, concentration or dosing relative to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. From the perspective of the medicinal chemist, the GRI is also important as a generalized model of a potentially new generation of therapeutics that adjust potency in response to a critical therapeutic marker. The aim of this Perspective is to highlight emerging concepts, including mathematical modelling and the molecular engineering of insulin itself and its potency, towards a viable GRI. We briefly outline some of the most important recent progress toward this goal and also provide a forward-looking viewpoint, which asks if there are new approaches that could spur innovation in this area as well as to encourage synthetic chemists and chemical engineers to address the challenges and promises offered by this therapeutic approach.
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Turkett, Jeremy A; Bicker, Kevin L
2017-04-10
Growing prevalence of antibiotic resistant bacterial infections necessitates novel antimicrobials, which could be rapidly identified from combinatorial libraries. We report the use of the peptoid library agar diffusion (PLAD) assay to screen peptoid libraries against the ESKAPE pathogens, including the optimization of assay conditions for each pathogen. Work presented here focuses on the tailoring of combinatorial peptoid library design through a detailed study of how peptoid lipophilicity relates to antibacterial potency and mammalian cell toxicity. The information gleaned from this optimization was then applied using the aforementioned screening method to examine the relative potency of peptoid libraries against Staphylococcus aureus, Acinetobacter baumannii, and Enterococcus faecalis prior to and following functionalization with long alkyl tails. The data indicate that overall peptoid hydrophobicity and not simply alkyl tail length is strongly correlated with mammalian cell toxicity. Furthermore, this work demonstrates the utility of the PLAD assay in rapidly evaluating the effect of molecular property changes in similar libraries.
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Xu, Y; Li, YF; Zhang, D; Dockendorf, M; Tetteh, E; Rizk, ML; Grobler, JA; Lai, M‐T; Gobburu, J
2016-01-01
We applied model‐based meta‐analysis of viral suppression as a function of drug exposure and in vitro potency for short‐term monotherapy in human immunodeficiency virus type 1 (HIV‐1)‐infected treatment‐naïve patients to set pharmacokinetic targets for development of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (InSTIs). We developed class‐specific models relating viral load kinetics from monotherapy studies to potency normalized steady‐state trough plasma concentrations. These models were integrated with a literature assessment of doses which demonstrated to have long‐term efficacy in combination therapy, in order to set steady‐state trough concentration targets of 6.17‐ and 2.15‐fold above potency for NNRTIs and InSTIs, respectively. Both the models developed and the pharmacokinetic targets derived can be used to guide compound selection during preclinical development and to predict the dose–response of new antiretrovirals to inform early clinical trial design. PMID:27171172
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Zhang, Miao; Pascal, John M.; Schumann, Marcel; Armen, Roger S.; Zhang, Ji-fang
2012-01-01
Small- and intermediate-conductance Ca2+-activated potassium channels, activated by Ca2+-bound calmodulin, play an important role in regulating membrane excitability. These channels are also linked to clinical abnormalities. A tremendous amount of effort has been devoted to developing small molecule compounds targeting these channels. However, these compounds often suffer from low potency and lack of selectivity, hindering their potentials for clinical use. A key contributing factor is the lack of knowledge of the binding site(s) for these compounds. Here we demonstrate by X-ray crystallography that the binding pocket for the compounds of the 1-EBIO class is located at the calmodulin-channel interface. We show that, based on structure data and molecular docking, mutations of the channel can effectively change the potency of these compounds. Our results provide insight into the molecular nature of the binding pocket and its contribution to the potency and selectivity of the compounds of the 1-EBIO class. PMID:22929778
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Zhang, Miao; Pascal, John M; Schumann, Marcel; Armen, Roger S; Zhang, Ji-Fang
2012-01-01
Small- and intermediate-conductance Ca(2+)-activated potassium channels, activated by Ca(2+)-bound calmodulin, have an important role in regulating membrane excitability. These channels are also linked to clinical abnormalities. A tremendous amount of effort has been devoted to developing small molecule compounds targeting these channels. However, these compounds often suffer from low potency and lack of selectivity, hindering their potential for clinical use. A key contributing factor is the lack of knowledge of the binding site(s) for these compounds. Here we demonstrate by X-ray crystallography that the binding pocket for the compounds of the 1-ethyl-2-benzimidazolinone (1-EBIO) class is located at the calmodulin-channel interface. We show that, based on structure data and molecular docking, mutations of the channel can effectively change the potency of these compounds. Our results provide insight into the molecular nature of the binding pocket and its contribution to the potency and selectivity of the compounds of the 1-EBIO class.
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AFIR: A Dimensionless Potency Metric for Characterizing the Activity of Monoclonal Antibodies
Ramakrishna, R
2017-01-01
For monoclonal antibody (mAb) drugs, soluble targets may accumulate several thousand fold after binding to the drug. Time course data of mAb and total target is often collected and, although free target is more closely related to clinical effect, it is difficult to measure. Therefore, mathematical models of this data are used to predict target engagement. In this article, a “potency factor” is introduced as an approximation for the model‐predicted target inhibition. This potency factor is defined to be the time‐Averaged Free target concentration to Initial target concentration Ratio (AFIR), and it depends on three key quantities: the average drug concentration at steady state; the binding affinity; and the degree of target accumulation. AFIR provides the intuition for how changes in dosing regimen and binding affinity affect target capture and AFIR can be used to predict the druggability of new targets and the expected benefits of more potent, second‐generation mAbs. PMID:28375563
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Sameshima, H; Ueda, T; Haruyama, E; Chihaya, Y; Mizushima, Y; Ueno, M; Moriyama, T; Kii, Y; Kato, I
2001-05-01
A six-month repeated oral dose toxicity study of Cefmatilen hydrochloride hydrate (S-1090) at dose levels of 40, 100 and 250 mg potency/kg/day was conducted in male and female beagle dogs. No toxicologically significant changes were observed in general conditions of all animals. Reddish-brown feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet) were observed in all treated groups. Plasma irons showed a tendency to increase in the males and females of the 250 mg potency/kg group. However, as no changes suggesting anemia or hepatic injury were observed in this group, the change of plasma iron was considered to have no toxicological significance. No toxicologically significant changes were observed in other examination items. The plasma S-1090 concentrations increased in a manner less than dose-proportional. Based on the above results, the NOAEL of S-1090 was assessed to be 250 mg potency/kg/day.
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n-Octyl gallate as inhibitor of pyruvate carboxylation and lactate gluconeogenesis.
Eler, Gabrielle Jacklin; Santos, Israel Souza; de Moraes, Amarilis Giaretta; Comar, Jurandir Fernando; Peralta, Rosane Marina; Bracht, Adelar
2015-04-01
The alkyl gallates are found in several natural and industrial products. In the latter products, these compounds are added mainly for preventing oxidation. In the present work, the potencies of methyl gallate, n-propyl gallate, n-pentyl gallate, and n-octyl gallate as inhibitors of pyruvate carboxylation and lactate gluconeogenesis were evaluated. Experiments were done with isolated mitochondria and the isolated perfused rat liver. The potency of the gallic acid esters as inhibitors of pyruvate carboxylation in isolated mitochondria obeyed the following decreasing sequence: n-octyl gallate > n-pentyl gallate > n-propyl gallate > methyl gallate. A similar sequence of decreasing potency for lactate gluconeogenesis inhibition in the perfused liver was found in terms of the portal venous concentration. Both actions correlate with the lipophilicity of the compounds. The effects are harmful at high concentrations. At appropriate concentrations, however, octyl gallate should act therapeutically because its inhibitory action on gluconeogenesis will contribute further to its proposed antihyperglycemic effects. © 2014 Wiley Periodicals, Inc.
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Confidence limit calculation for antidotal potency ratio derived from lethal dose 50
Manage, Ananda; Petrikovics, Ilona
2013-01-01
AIM: To describe confidence interval calculation for antidotal potency ratios using bootstrap method. METHODS: We can easily adapt the nonparametric bootstrap method which was invented by Efron to construct confidence intervals in such situations like this. The bootstrap method is a resampling method in which the bootstrap samples are obtained by resampling from the original sample. RESULTS: The described confidence interval calculation using bootstrap method does not require the sampling distribution antidotal potency ratio. This can serve as a substantial help for toxicologists, who are directed to employ the Dixon up-and-down method with the application of lower number of animals to determine lethal dose 50 values for characterizing the investigated toxic molecules and eventually for characterizing the antidotal protections by the test antidotal systems. CONCLUSION: The described method can serve as a useful tool in various other applications. Simplicity of the method makes it easier to do the calculation using most of the programming software packages. PMID:25237618
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Dallanoce, C; Conti, P; De Amici, M; De Micheli, C; Barocelli, E; Chiavarini, M; Ballabeni, V; Bertoni, S; Impicciatore, M
1999-08-01
Two subseries of nonquaternized (5a-10a) and quaternized derivatives (5b-10b) related to oxotremorine and oxotremorine-M were synthesized and tested. The agonist potency at the muscarinic receptor subtypes of the new compounds was estimated in three classical in vitro functional assays: M1 rabbit vas deferens, M2 guinea pig left atrium and M3 guinea pig ileum. In addition, the occurrence of central muscarinic effects was evaluated as tremorigenic activity after intraperitoneal administration in mice. In in vitro tests a nonselective muscarinic activity was exhibited by all the derivatives with potencies values that, in some instances, surpassed those of the reference compounds (i.e. 8b). Functional selectivity was evidenced only for the oxotremorine-like derivative 9a, which behaved as a mixed M3-agonist/M1-antagonist (pD2 = 5.85; pA2 = 4.76, respectively). In in vivo tests non-quaternary compounds were able to evoke central muscarinic effects, with a potency order parallel to that observed in vitro.
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Bosak, Anita; Knežević, Anamarija; Gazić Smilović, Ivana; Šinko, Goran; Kovarik, Zrinka
2017-12-01
We investigated the influence of bronchodilating β2-agonists on the activity of human acetylcholinesterase (AChE) and usual, atypical and fluoride-resistant butyrylcholinesterase (BChE). We determined the inhibition potency of racemate and enantiomers of fenoterol as a resorcinol derivative, isoetharine and epinephrine as catechol derivatives and salbutamol and salmeterol as saligenin derivatives. All of the tested compounds reversibly inhibited cholinesterases with K i constants ranging from 9.4 μM to 6.4 mM and had the highest inhibition potency towards usual BChE, but generally none of the cholinesterases displayed any stereoselectivity. Kinetic and docking results revealed that the inhibition potency of the studied compounds could be related to the size of the hydroxyaminoethyl chain on the benzene ring. The additional π-π interaction of salmeterol's benzene ring and Trp286 and hydrogen bond with His447 probably enhanced inhibition by salmeterol which was singled out as the most potent inhibitor of all the cholinesterases.
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Corbett, J W; Ko, S S; Rodgers, J D; Jeffrey, S; Bacheler, L T; Klabe, R M; Diamond, S; Lai, C M; Rabel, S R; Saye, J A; Adams, S P; Trainor, G L; Anderson, P S; Erickson-Viitanen, S K
1999-12-01
A research program targeted toward the identification of expanded-spectrum nonnucleoside reverse transcriptase inhibitors which possess increased potency toward K103N-containing mutant human immunodeficiency virus (HIV) and which maintain pharmacokinetics consistent with once-a-day dosing has resulted in the identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 082 and DPC 083 for clinical development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar potency toward wild-type virus, K103N and L100I single-mutation variants, and many multiply amino acid-substituted HIV type 1 mutants. This high degree of potency is combined with a high degree of oral bioavailability, as demonstrated in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can result in significant free levels of drug.
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Luethi, Dino; Liechti, Matthias E
2018-05-29
Pharmacological profiles of new psychoactive substances (NPSs) can be established rapidly in vitro and provide information on potential psychoactive effects in humans. The present study investigated whether specific in vitro monoamine transporter and receptor interactions can predict effective psychoactive doses in humans. We correlated previously assessed in vitro data of stimulants and psychedelics with human doses that are reported on the Internet and in books. For stimulants, dopamine and norepinephrine transporter inhibition potency was positively correlated with human doses, whereas serotonin transporter inhibition potency was inversely correlated with human doses. Serotonin 5-hydroxytryptamine-2A (5-HT2A) and 5-HT2C receptor affinity was significantly correlated with psychedelic doses, but 5-HT1A receptor affinity and 5-HT2A and 5-HT2B receptor activation potency were not. The rapid assessment of in vitro pharmacological profiles of NPSs can help to predict psychoactive doses and effects in humans and facilitate the appropriate scheduling of NPSs.
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Collective autonomy and absenteeism within work teams: a team motivation approach.
Rousseau, Vincent; Aubé, Caroline
2013-01-01
This study investigates the role of collective autonomy in regard to team absenteeism by considering team potency as a motivational mediator and task routineness as a moderator. The sample consists of 90 work teams (327 members and 90 immediate superiors) drawn from a public safety organization. Results of structural equation modeling indicate that the relationships between collective autonomy and two indicators of team absenteeism (i.e., absence frequency and time lost) are mediated by team potency. Specifically, collective autonomy is positively related to team potency which in turn is negatively related to team absenteeism. Furthermore, results of hierarchical regression analyses show that task routineness moderates the relationships between collective autonomy and the two indicators of team absenteeism such that these relationships are stronger when the level of task routineness is low. On the whole, this study points out that collective autonomy may exercise a motivational effect on attendance at work within teams, but this effect is contingent on task routineness.
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Fragment-wise design of inhibitors to 3C proteinase from enterovirus 71.
Wu, Caiming; Zhang, Lanjun; Li, Peng; Cai, Qixu; Peng, Xuanjia; Yin, Ke; Chen, Xinsheng; Ren, Haixia; Zhong, Shilin; Weng, Yuwei; Guan, Yi; Chen, Shuhui; Wu, Jinzhun; Li, Jian; Lin, Tianwei
2016-06-01
Enterovirus 71 (EV71) is a causative agent of hand, foot and mouth disease (HFMD), which can spread its infection to central nervous and other systems with severe consequence. A key factor in the replication of EV71 is its 3C proteinase (3C(pro)), a significant drug target. Peptidomimetics were employed as inhibitors of this enzyme for developing antivirals. However, the peptide bonds in these peptidomimetics are a source of low bioavailability due to their susceptibility to protease digestion. To produce non-peptidomimetic inhibitors by replacing these peptide bonds, it would be important to gain better understanding on the contribution of each component to the interaction and potency. A series of compounds of different lengths targeting 3C(pro) and having an α,β-unsaturated ester as the warhead were synthesized and their interactions with the enzyme were evaluated by complex structure analyses and potency assays for a better understanding on the relationship between potency and evolution of interaction. The P2 moiety of the compound would need to be oriented to interact in the S2 site in the substrate binding cleft and the P3-P4 moieties were required to generate sufficient potency. A hydrophobic terminal group will benefit the cellular uptake and improve the activity in vivo. The data presented here provide a basis for designing a new generation of non-peptidomimetics to target EV71 3C(pro). Copyright © 2016 Elsevier B.V. All rights reserved.
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A novel antilithiatic protein from Tribulus terrestris having cytoprotective potency.
Aggarwal, Anshu; Tandon, Simran; Singla, Surinder Kumar; Tandon, Chanderdeep
2012-08-01
Adhesion of calcium oxalate (CaOx) crystals to kidney cells is a key event in kidney stones associated with marked hyperoxaluria. As the propensity of stone recurrence and persistent side effects are not altered by surgical techniques available, phytotherapeutic agents could be useful as an adjuvant therapy. The present study is aimed at examining the antilithiatic potency of the protein biomolecules of Tribulus terrestris, a plant which is a common constituent of herbal marketed preparations to treat urolithiasis. Various biochemical methods with mass spectrometry were used to purify and characterize the purified protein. The protective potency of the protein was tested on the oxalate induced injury on renal epithelial cell lines (NRK 52E). An antilithiatic protein having molecular weight of ~ 60kDa was purified. This purified protein showed similarities with Carotenoid cleavage dioxygenase 7 (CCD7) of Arabidopsis thaliana after matching peptide mass fingerprints in MASCOT search engine. An EF hand domain was identified in CCD7 by SCAN PROSITE. Presence of an EF hand domain, a characteristic feature of calcium binding proteins and a role in the synthesis of retinol which is transported by retinol binding protein, a protein found in kidney stone matrix; of CCD7 support the role of TTP as an antilithiatic protein. The protective potency of TTP on NRK 52E was quite comparable to the aqueous extract of cystone. Our findings suggest that this purified protein biomolecule from Tribulus terrestris could open new vista in medical management of urolithiasis.
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Yamano, Tetsuo; Shimizu, Mitsuru
2009-04-01
p-Phenylenediamine (PPD)-related chemicals have been used as antioxidants in rubber products, and many cases of contact dermatitis caused by these chemicals have been reported. The aim of this study was to investigate relative sensitizing potency and cross-reactivity among PPD derivatives. Five PPD derivatives, p-aminodiphenylamine (PADPA), N,N'-diphenyl-p-phenylenediamine (DPPD), N-isopropyl-N'-phenyl-p-phenylenediamine (IPPD), N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (DMBPPD), N-(1-methylheptyl)-N'-phenyl-p-phenylenediamine (MHPPD), and the core chemical PPD were evaluated for their sensitizing potency and cross-reactivity using the non-radioactive murine local lymph node assay (LLNA) and the guinea-pig maximization test (GPMT). PPD and all the derivatives were identified as primary sensitizers in both tests. The order of potency in the LLNA was as follows: IPPD and PADPA > PPD > DMBPPD and MHPPD > DPPD. In the GPMT, all six groups of animals sensitized with one of these chemicals cross-reacted to four other derivatives. Specifically, the five groups that have a common basic PADPA structure, that is PADPA, DPPD, IPPD, DMBPPD, and MHPPD, all reacted to each other at almost the same scores, while none of them reacted to PPD. The cross-reactivity profile found in the study was to some extent different from that in previous human data, where distinction between cross-reaction and concomitant primary sensitization is not always clear.
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Takeyoshi, Masahiro; Iida, Kenji; Suzuki, Keiko; Yamazaki, Shunsuke
2008-05-01
Allergic contact dermatitis is the serious unwanted effect arising from the use of consumer products such as cosmetics. Isoeugenol is a fragrance chemical with spicy, carnation-like scent, is used in many kinds of cosmetics and is a well-known moderate human sensitizer. It was previously reported that the dimerization of eugenol yielded two types of dimer possessing different sensitization potencies. This study reports the differences in skin sensitization potencies for isoeugenol and two types of dimer, beta-O-4-dilignol and dehydrodiisoeugenol (DIEG), as evaluated by the non-radioisotopic local lymph node assay (non-RI LLNA) and guinea pig maximization test. In the guinea pig maximization test, isoeugenol, beta-O-4-dilignol and DIEG were classified as extreme, weak and moderate sensitizers, respectively. As for the results of non-RI LLNA, the EC3 for isoeugenol, beta-O-4-dilignol and DIEG were calculated as 12.7%, >30% and 9.4%, respectively. The two types of isoeugenol dimer showed different sensitizing activities similar to the case for eugenol dimers. A reduction of sensitization potency achieved by dimerization may lead to developing safer cosmetic ingredients. Isoeugenol dimers are not currently used for fragrance chemicals. However, the dimerization of isoeugenol may yield a promising candidate as a cosmetic ingredient with low sensitization risk. The data may also provide useful information for the structure-activity relationship (SAR) in skin sensitization. Copyright (c) 2007 John Wiley & Sons, Ltd.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Goebel, Carsten, E-mail: goebel.c.1@pg.com; Troutman, John; Hennen, Jenny
The strong sensitizing potencies of the most important primary intermediates of oxidative hair dyes, p-phenylenediamine (PPD) and p-toluylenediamine (PTD, i.e. 2-methyl-PPD) are well established. They are considered as the key sensitizers in hair dye allergic contact dermatitis. While modification of their molecular structure is expected to alter their sensitizing properties, it may also impair their color performance. With introduction of a methoxymethyl side chain we found the primary intermediate 2-methoxymethyl-p-phenylenediamine (ME-PPD) with excellent hair coloring performance but significantly reduced sensitizing properties compared to PPD and PTD: In vitro, ME-PPD showed an attenuated innate immune response when analyzed for its proteinmore » reactivity and dendritic cell activation potential. In vivo, the effective concentration of ME-PPD necessary to induce an immune response 3-fold above vehicle control (EC3 value) in the local lymph node assay (LLNA) was 4.3%, indicating a moderate skin sensitizing potency compared to values of 0.1 and 0.17% for PPD and PTD, respectively. Finally, assessing the skin sensitizing potency of ME-PPD under consumer hair dye usage conditions through a quantitative risk assessment (QRA) indicated an allergy induction risk negligible compared to PPD or PTD. - Highlights: • Methoxymethyl side chain in p-phenylenediamine reduces its strong skin sensitizing properties. • Reduced protein reactivity and dendritic cell activation. • Reduced skin sensitizing potency in local lymph node assay (LLNA). • Negligible allergy induction risk under hair dye usage conditions.« less
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Shi, Wei; Zhang, Feng-Xian; Hu, Guan-Jiu; Hao, Ying-Qun; Zhang, Xiao-Wei; Liu, Hong-Ling; Wei, Si; Wang, Xin-Ru; Giesy, John P; Yu, Hong-Xia
2012-07-01
Thyroid hormone disrupting compounds in water sources is a concern. Thyroid hormone (TH) agonist and antagonist activities of water sources from the Yangtze River, Huaihe River, Taihu Lake and ground water in the Yangtze River Delta region were evaluated by use of a TH reporter gene assay based on the green monkey kidney fibroblast (CV-1). While weak TH receptor (TR) agonist potency was observed in only one of 15 water sources, antagonist potency was present in most of the water sources. TR antagonist equivalents could be explained by the presence of dibutyl phthalate (DBP), with concentrations ranging from 2.8×10(1) to 1.6×10(3) μg DBP /L (ATR-EQ(50)s). None of the ground waters exhibited TH agonist potencies while all of the samples from Taihu Lake displayed notable TR antagonist potencies. To identify the responsible thyroid active compounds, instrumental analysis was conducted to measure a list of potential thyroid-disrupting chemicals, including organochlorine (OC) pesticides and phthalate esters. Combining the results of the instrumental analysis with those of the bioassay, DBP was determined to account for 17% to 144% of ATR-EQ(50)s in water sources. Furthermore, ATR-EQ(20-80) ranges for TR antagonist activities indicated that samples from locations WX-1 and WX-2 posed the greatest health concern and the associated uncertainty may warrant further investigation. Copyright © 2011 Elsevier Ltd. All rights reserved.