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Find video protocols related to scientific articles indexed in Pubmed.
Safety Assessment of Animal- and Plant-Derived Amino Acids as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 10-18-2014
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of animal- and plant-derived amino acid mixtures, which function as skin and hair conditioning agents. The safety of ?-amino acids as direct food additives has been well established, based on extensive research through acute and chronic dietary exposures and the Panel previously has reviewed the safety of individual ?-amino acids in cosmetics. The Panel focused its review on dermal irritation and sensitization data relevant to the use of these ingredients in topical cosmetics. The Panel concluded that these 21 ingredients are safe in the present practices of use and concentration as used in cosmetics.
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Amended safety assessment of hypericum perforatum-derived ingredients as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 10-10-2014
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The Cosmetic Ingredient Review Expert Panel (Panel) has issued an amended safety assessment of 7 Hypericum perforatum-derived ingredients as used in cosmetics. A common name for this plant is St John wort. These ingredients function in cosmetics as skin-conditioning agents-miscellaneous and antimicrobial agents. The Panel reviewed relevant animal and human data related to the H perforatum-derived ingredients. Because formulators may use more than 1 botanical ingredient in a formulation, caution was urged to avoid levels of toxicological concern for constituent chemicals and impurities. The Panel concluded that H perforatum-derived ingredients were safe as cosmetic ingredients in the practices of use and concentration as described in this safety assessment.
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Safety Assessment of Vitis vinifera (Grape)-Derived Ingredients as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 10-10-2014
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The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of 24 Vitis vinifera (grape)-derived ingredients and found them safe in the present practices of use and concentration in cosmetics. These ingredients function in cosmetics mostly as skin-conditioning agents, but some function as antioxidants, flavoring agents, and/or colorants. The Panel reviewed the available animal and clinical data to determine the safety of these ingredients. Additionally, some constituents of grapes have been assessed previously for safety as cosmetic ingredients by the Panel, and others are compounds that have been discussed in previous Panel safety assessments.
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Safety assessment of modified terephthalate polymers as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 10-10-2014
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The safety of 6 modified terephthalate polymers as cosmetic ingredients was assessed. These ingredients mostly function as exfoliants, bulking agents, hair fixatives, and viscosity-increasing agents-nonaqueous. Polyethylene terephthalate (PET) is used in leave-on products up to 100% and in rinse-off products up to 2%. The Cosmetic Ingredient Review Expert Panel (Panel) considered that the PET used in cosmetics is chemically equivalent to that used in medical devices. The Panel determined that the Food and Drug Administration's determination of safety of PET in several medical devices, which included human and animal safety data, can be used as the basis for the determination of safety of PET and related polymers used in cosmetics. Use studies of cosmetic eye products that contain PET demonstrated no ocular irritation or dermal sensitization. The Panel concluded that modified terephthalate polymers were safe as cosmetic ingredients in the practices of use and concentration described in this safety assessment.
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Safety assessment of 6-hydroxyindole as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 10-10-2014
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 6-hydroxyindole, which functions as an oxidative hair dye ingredient. The Panel considered relevant animal and human data provided in this safety assessment and concluded that 6-hydroxyindole is safe for use in oxidative hair dye formulations.
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Safety Assessment of PEGylated Oils as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 08-27-2014
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PEGylated oil is a terminology used to describe cosmetic ingredients that are the etherification and esterification products of glycerides and fatty acids with ethylene oxide. The Cosmetic Ingredient Review Expert Panel (Panel) considered the safety of PEGylated oils, which function primarily as surfactants in cosmetic products. The Panel reviewed relevant animal and human data provided in this safety assessment and concluded that the 130 chemically related PEGylated oils were safe as cosmetic ingredients in the present practices of use and concentration when formulated to be nonirritating.
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Safety Assessment of Dimethicone Crosspolymers as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-28-2014
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 62 dimethicone crosspolymer ingredients as used in cosmetics. These ingredients function mostly as absorbents, bulking agents, film formers, hair-conditioning agents, emollient skin-conditioning agents, slip modifiers, surface modifiers, and nonaqueous viscosity-increasing agents. The Panel reviewed available animal and human data related to these polymers and addressed the issue of residual monomers. The Panel concluded that these dimethicone crosspolymer ingredients are safe in the practices of use and concentration as given in this safety assessment.
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Safety Assessment of Chlorphenesin as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-28-2014
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Chlorphenesin functions as a biocide in cosmetics and is used at concentrations up to 0.32% in rinse-off products and up to 0.3% in leave-on products. The Cosmetic Ingredient Review Expert Panel (Panel) noted that chlorphenesin was well absorbed when applied to the skin of rats; however, any safety concern was minimized because available data demonstrated an absence of toxicity. The Panel concluded that chlorphenesin is safe in the present practices of use and concentration.
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Safety Assessment of Cucumis sativus (Cucumber)-Derived Ingredients as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-28-2014
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The CIR Expert Panel assessed the safety of 6 Cucumis sativus (cucumber)-derived ingredients and found them safe in cosmetic formulations in the present practices of use and concentration. These ingredients are reported to function in cosmetics as skin-conditioning agents. Cucumber is a commonly consumed food with no history of significant adverse effects, suggesting that its ingredients should not pose any major safety issues following oral exposure. This assessment focused on the dermal exposure to the low concentrations of these ingredients as used in cosmetics. Some of the constituents of cucumbers have been assessed previously for safe use as cosmetic ingredients.
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Safety Assessment of Citric Acid, Inorganic Citrate Salts, and Alkyl Citrate Esters as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-28-2014
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The CIR Expert Panel (Panel) assessed the safety of citric acid, 12 inorganic citrate salts, and 20 alkyl citrate esters as used in cosmetics, concluding that these ingredients are safe in the present practices of use and concentration. Citric acid is reported to function as a pH adjuster, chelating agent, or fragrance ingredient. Some of the salts are also reported to function as chelating agents, and a number of the citrates are reported to function as skin-conditioning agents but other functions are also reported. The Panel reviewed available animal and clinical data, but because citric acid, calcium citrate, ferric citrate, manganese citrate, potassium citrate, sodium citrate, diammonium citrate, isopropyl citrate, stearyl citrate, and triethyl citrate are generally recognized as safe direct food additives, dermal exposure was the focus for these ingredients in this cosmetic ingredient safety assessment.
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Structure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis.
J. Med. Chem.
PUBLISHED: 04-10-2014
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Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.
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Unprecedented conformational flexibility revealed in the ligand-binding domains of the Bovicola ovis ecdysone receptor (EcR) and ultraspiracle (USP) subunits.
Acta Crystallogr. D Biol. Crystallogr.
PUBLISHED: 03-28-2014
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The heterodimeric ligand-binding region of the Bovicola ovis ecdysone receptor has been crystallized either in the presence of an ecdysteroid or a synthetic methylene lactam insecticide. Two X-ray crystallographic structures, determined at 2.7?Å resolution, show that the ligand-binding domains of both subunits of this receptor, like those of other nuclear receptors, can display significant conformational flexibility. Thermal melt experiments show that while ponasterone A stabilizes the higher order structure of the heterodimer in solution, the methylene lactam destabilizes it. The conformations of the EcR and USP subunits observed in the structure crystallized in the presence of the methylene lactam have not been seen previously in any ecdysone receptor structure and represent a new level of conformational flexibility for these important receptors. Interestingly, the new USP conformation presents an open, unoccupied ligand-binding pocket.
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Amended safety assessment of formaldehyde and methylene glycol as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 12-17-2013
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Formaldehyde and methylene glycol may be used safely in cosmetics if established limits are not exceeded and are safe for use in nail hardeners in the present practices of use and concentration, which include instructions to avoid skin contact. In hair-smoothing products, however, in the present practices of use and concentration, formaldehyde and methylene glycol are unsafe. Methylene glycol is continuously converted to formaldehyde, and vice versa, even at equilibrium, which can be easily shifted by heating, drying, and other conditions to increase the amount of formaldehyde. This rapid, reversible formaldehyde/methylene glycol equilibrium is distinguished from the slow, irreversible release of formaldehyde resulting from the so-called formaldehyde releaser preservatives, which are not addressed in this safety assessment (formaldehyde releasers may continue to be safely used in cosmetics at the levels established in their individual Cosmetic Ingredient Review safety assessments).
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Safety Assessment of ?-Amino Acids as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 12-17-2013
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of ?-amino acids, which function primarily as hair- and skin-conditioning agents in cosmetic products. The safety of ?-amino acids as direct food additives has been well established based on extensive research through acute and chronic dietary exposures. The Panel focused its review on dermal irritation and sensitization data relevant to the use of these ingredients in topical cosmetics. The Panel concluded that ?-amino acids were safe as cosmetic ingredients in the practices of use and concentration of this safety assessment.
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Safety assessment of ammonium hectorites as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 12-17-2013
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 4 ammonium hectorite compounds used in cosmetics: disteardimonium hectorite, dihydrogenated tallow benzylmonium hectorite, stearalkonium hectorite, and quaternium-18 hectorite. These ingredients function in cosmetics mainly as nonsurfactant suspending agents. The Panel reviewed available animal and human data and concluded that these ammonium hectorite compounds were safe as cosmetic ingredients in the practices of use and concentration as given in this safety assessment.
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Safety assessment of borosilicate glasses as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-01-2013
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of calcium sodium borosilicate, calcium aluminum borosilicate, calcium titanium borosilicate, silver borosilicate, and zinc borosilicate as used in cosmetics. These borosilicate glasses function mostly as bulking agents. Available animal and human data were considered along with data from a previous safety assessment of magnesium silicates. The similar structure, properties, functions, and uses of these ingredients enabled grouping them and using the available toxicological data to assess the safety of the entire group. Data submitted on calcium borosilicate, which is not a cosmetic ingredient, are also included as additional support for the safety of borosilicate glass ingredients. The Panel concluded that borosilicate glasses are safe as cosmetic ingredients in the practices of use and concentration as given in this safety assessment.
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Safety assessment of alkyl glyceryl ethers as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-01-2013
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Alkyl glyceryl ethers function mostly as skin-conditioning agents in cosmetic products applied to the skin and hair. The Cosmetic Ingredient Review expert panel reviewed the available animal toxicity and clinical data, including the low dermal absorption, and concluded that the alkyl glyceryl ethers are safe in the present practices of use and concentration described in this safety assessment.
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Safety assessment of bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-01-2013
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The Cosmetic Ingredient Review Expert Panel assessed the safety of bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used in cosmetics, finding that these ingredients are safe in cosmetic formulations in the present practices of use and concentration. Both ingredients are lanolin substitutes and are reported to function in cosmetics as skin-conditioning agents--emollients. The Panel reviewed available animal and clinical data in making its determination of safety.
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Safety assessment of lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-01-2013
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The Cosmetic Ingredient Review Expert Panel assessed the safety of lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate as used in cosmetics. These ingredients function in cosmetics as hair-conditioning agents and surfactant-cleansing agents. The Panel reviewed relevant animal and human data related to the safety of these ingredients in cosmetics. The Panel concluded that lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate are safe as cosmetic ingredients in the present practices of use and concentration.
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Safety assessment of decyl glucoside and other alkyl glucosides as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-01-2013
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The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of 19 alkyl glucosides as used in cosmetics and concluded that these ingredients are safe in the present practices of use and concentration when formulated to be nonirritating. Most of these ingredients function as surfactants in cosmetics, but some have additional functions as skin-conditioning agents, hair-conditioning agents, or emulsion stabilizers. The Panel reviewed the available animal and clinical data on these ingredients. Since glucoside hydrolases in human skin are likely to break down these ingredients to release their respective fatty acids and glucose, the Panel also reviewed CIR reports on the safety of fatty alcohols and were able to extrapolate data from those previous reports to support safety.
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B-cell antigen receptor signaling in chronic lymphocytic leukemia: therapeutic targets and translational opportunities.
Int. Rev. Immunol.
PUBLISHED: 07-27-2013
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B-cell chronic lymphocytic leukemia (CLL) is characterized by clonally expanded and molecularly heterogeneous populations of B lymphocytes with impaired apoptotic mechanisms. This occurs as a result of multiple genetic and epigenetic abnormalities, including chromosomal aberrations and enhancer region hypomethylation, often impinging on intracellular signaling pathways that are essential to normal B-cell activation, proliferation, and survival. The B-cell antigen receptor (BCR) signaling is one such pathway usurped by malignant B cells, as exemplified by the early phase clinical success achieved by small-molecule agents targeting key players involved in the pathway. Such new targeted agents, including those that inhibit the function of Spleen tyrosine kinase (SYK), Brutons tyrosine kinase (BTK), phosphatidylinositol 3-kinases (PI3K), and B-cell lymphoma 2 (BCL-2), along with the current standard therapy comprising chemo-immunotherapies with or without B-cell depleting biologic agent rituximab (anti-CD20 monoclonal antibody), should expand the armamentarium for CLL therapy. We review the therapeutic agents currently in clinical development which target different effectors of the malignant BCR signaling, and discuss their overlapping and discriminating translational opportunities in the context of CLL treatment.
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Safety assessment of silylates and surface-modified siloxysilicates.
Int. J. Toxicol.
PUBLISHED: 05-23-2013
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The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of silica silylate, silica dimethyl silylate, trimethylsiloxysilicate, and trifluoropropyldimethyl/trimethylsiloxysilicate as used in cosmetics. These silylates and surface-modified siloxysilicates function in cosmetics as antifoaming agents, anticaking agents, bulking agents, binders, skin-conditioning agents--emollient, skin-conditioning agents-occlusive, slip modifiers, suspension agents--nonsurfactant, and viscosity increasing agents--nonaqueous. The Expert Panel reviewed the available animal and clinical data as well as information from a previous CIR safety assessment of amorphous silica. The CIR Expert Panel concluded that silica silylate, silica dimethyl silylate, trimethylsiloxysilicate, and trifluoropropyldimethyl/trimethylsiloxysilicate are safe as used when formulated and delivered in the final product not to be irritating or sensitizing to the respiratory tract.
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Safety assessment of triethanolamine and triethanolamine-containing ingredients as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-23-2013
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The Cosmetic Ingredient Review Expert Panel assessed the safety of triethanolamine (TEA) and 31 related TEA-containing ingredients as used in cosmetics. The TEA is reported to function as a surfactant or pH adjuster; the related TEA-containing ingredients included in this safety assessment are reported to function as surfactants and hair- or skin-conditioning agents. The exception is TEA-sorbate, which is reported to function as a preservative. The Panel reviewed the available animal and clinical data. Although data were not available for all the ingredients, the panel relied on the information available for TEA in conjunction with previous safety assessments of components of TEA-containing ingredients. These data could be extrapolated to support the safety of all included ingredients. The panel concluded that TEA and related TEA-containing ingredients named in this report are safe as used when formulated to be nonirritating. These ingredients should not be used in cosmetic products in which N-nitroso compounds can be formed.
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Safety assessment of diethanolamides as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-23-2013
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Cocamide diethanolamine (DEA) and some of the other diethanolamides are mainly used as surfactant foam boosters or viscosity increasing agents in cosmetics, although a few are reported to be used as hair and skin conditioning agents, surfactant-cleansing or surfactant-emulsifying agents, or as an opacifying agent. The Cosmetic Ingredient Review (CIR) Expert Panel considered new data and information from previous CIR reports to assess the concerns about the potential for amidases in human skin to convert these diethanolamides into DEA and the corresponding fatty acids. The Expert Panel concluded that these diethanolamides are safe as used when formulated to be nonirritating and when the levels of free DEA in the diethanolamides do not exceed those considered safe by the Panel. The Panel also recommended that these ingredients not be used in cosmetic products in which N-nitroso compounds can be formed.
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Safety assessment of 2-amino-4-hydroxyethylaminoanisole and 2-amino-4-hydroxyethylaminoanisole sulfate as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-23-2013
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2-Amino-4-hydroxyethylaminoanisole and its salt, 2-amino-4-hydroxyethylaminoanisole sulfate, are used as coupling agents in oxidative hair dyes. The Cosmetic Ingredient Review Expert Panel reviewed relevant animal and human data related to the ingredient. The Expert Panel concluded that 2-amino-4-hydroxyethylaminoanisole and 2-amino-4-hydroxyethylaminoanisole sulfate are safe for use in oxidative hair dye formulations. The Expert Panel cautioned that these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed.
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Saphenous vein graft failure and clinical outcomes: toward a surrogate end point in patients following coronary artery bypass surgery?
Am. Heart J.
PUBLISHED: 01-17-2013
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Saphenous vein graft (SVG) failure is a common finding in patients following coronary artery bypass graft (CABG) surgery. In the literature SVG failure rates have been reported from 25 to over 50% within 10 years. Although common, it remains unclear to what extent SVG failure affects clinical outcome, due to differences in definition, patient selection and follow-up. Particularly the lack of agreement on a universal definition makes comparisons between studies, and therefore generalizability of associations with outcomes, challenging. We suggest using a definition of SVG failure that is based on imaging as well as clinical parameters, that includes reporting SVG failure on both graft and patient level. The use of non-invasive imaging may help improve follow-up rates, and provide a more accurate picture of the real incidence and clinical impact of SVG failure. Given the lack of supportive evidence showing a consistent association between SVG failure and major adverse cardiovascular events, SVG failure should not be considered a valid surrogate endpoint at this time.
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Ceramide glycosylation catalyzed by glucosylceramide synthase and cancer drug resistance.
Adv. Cancer Res.
PUBLISHED: 01-08-2013
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Glucosylceramide synthase (GCS), converting ceramide to glucosylceramide, catalyzes the first reaction of ceramide glycosylation in sphingolipid metabolism. This glycosylation by GCS is a critical step regulating the modulation of cellular activities by controlling ceramide and glycosphingolipids (GSLs). An increase of ceramide in response to stresses, such as chemotherapy, drives cells to proliferation arrest and apoptosis or autophagy; however, ceramide glycosylation promptly eliminates ceramide and consequently, these induced processes, thus protecting cancer cells. Further, persistently enhanced ceramide glycosylation can increase GSLs, participating in selecting cancer cells to drug resistance. GCS is overexpressed in diverse drug-resistant cancer cells and in tumors of breast, colon, and leukemia that display poor response to chemotherapy. As ceramide glycosylation by GCS is a rate-limiting step in GSL synthesis, inhibition of GCS sensitizes cancer cells to anticancer drugs and eradicates cancer stem cells. Mechanistic studies indicate that uncoupling ceramide glycosylation can modulate gene expression, decreasing MDR1 through the cSrc/?-catenin pathway and restoring p53 expression via RNA splicing. These studies not only expand our knowledge in understanding how ceramide glycosylation affects cancer cells but also provide novel therapeutic approaches for targeting refractory tumors.
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Safety assessment of xylene sulfonic acid, toluene sulfonic acid, and alkyl aryl sulfonate hydrotropes as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 12-21-2011
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Xylene sulfonic acid, toluene sulfonic acid, and alkyl aryl sulfonate hydrotropes used in cosmetics as surfactants, hydrotropes, were reviewed in this safety assessment. The similar structure, properties, functions, and uses of these ingredients enabled grouping them and using the available toxicological data to assess the safety of the entire group. The Cosmetic Ingredient Review Expert Panel reviewed relevant animal and human data related to these ingredients. The panel concluded that xylene sulfonic acid and alkyl aryl sulfonate hydrotropes are safe as cosmetic ingredients in the present practices of use and concentrations as described in this safety assessment, when formulated to be nonirritating.
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Final report of the Cosmetic Ingredient Review Expert Panel on the safety assessment of pelargonic acid (nonanoic acid) and nonanoate esters.
Int. J. Toxicol.
PUBLISHED: 12-21-2011
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Pelargonic acid and its esters function as skin-conditioning agents in cosmetics. Molecular weight (mw) and octanol-water partition coefficient data suggest that dermal penetration is possible. The biohandling of branched-chain fatty acids is not the same as for straight-chain fatty acids, but the differences are not significant to the conclusion that they all are readily metabolized to nontoxic moieties. Limited data suggested that the penetration of other ingredients may be enhanced if these ingredients are present in the same formulation. These ingredients are not significant oral or dermal toxicants in animal studies. They are not reproductive/developmental toxicants or genotoxic/carcinogenic in animal studies. The available data suggested that product formulations containing these ingredients would be nonirritating and nonsensitizing to human skin, but formulators were cautioned to consider the penetration enhancement potential. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that these ingredients are safe in the present practices of use and concentration.
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Safety assessment of cyclomethicone, cyclotetrasiloxane, cyclopentasiloxane, cyclohexasiloxane, and cycloheptasiloxane.
Int. J. Toxicol.
PUBLISHED: 12-21-2011
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Cyclomethicone (mixture) and the specific chain length cyclic siloxanes (n = 4-7) reviewed in this safety assessment are cyclic dimethyl polysiloxane compounds. These ingredients have the skin/hair conditioning agent function in common. Minimal percutaneous absorption was associated with these ingredients and the available data do not suggest skin irritation or sensitization potential. Also, it is not likely that dermal exposure to these ingredients from cosmetics would cause significant systemic exposure. The Cosmetic Ingredient Review Expert Panel concluded that these ingredients are safe in the present practices of use and concentration.
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Final report of the Amended Safety Assessment of PVM/MA copolymer and its related salts and esters as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-10-2011
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Polyvinyl methyl ether/maleic acid (PVM/MA) copolymer, and its related salts and esters, are used in cosmetics, mainly as binders, film formers, and hair fixatives. Animal and human data relevant to the use of these ingredients in cosmetic products were reviewed by the CIR Expert Panel. The Panel concluded that these ingredients are safe for use in cosmetic products.
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Medicinal chemistry for 2020.
Future Med Chem
PUBLISHED: 10-19-2011
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Rapid advances in our collective understanding of biomolecular structure and, in concert, of biochemical systems, coupled with developments in computational methods, have massively impacted the field of medicinal chemistry over the past two decades, with even greater changes appearing on the horizon. In this perspective, we endeavor to profile some of the most prominent determinants of change and speculate as to further evolution that may consequently occur during the next decade. The five main angles to be addressed are: protein-protein interactions; peptides and peptidomimetics; molecular diversity and pharmacological space; molecular pharmacodynamics (significance, potential and challenges); and early-stage clinical efficacy and safety. We then consider, in light of these, the future of medicinal chemistry and the educational preparation that will be required for future medicinal chemists.
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Final report of the Cosmetic Ingredient Review Expert Panel safety assessment of polymethyl methacrylate (PMMA), methyl methacrylate crosspolymer, and methyl methacrylate/glycol dimethacrylate crosspolymer.
Int. J. Toxicol.
PUBLISHED: 07-21-2011
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Polymethyl methacrylate (PMMA) and related cosmetic ingredients methyl methacrylate crosspolymer and methyl methacrylate/glycol dimethacrylate crosspolymer are polymers that function as film formers and viscosity-increasing agents in cosmetics. The Food and Drug Administration (FDA) determination of safety of PMMA use in several medical devices, which included human and animal safety data, was used as the basis of safety of PMMA and related polymers in cosmetics by the Cosmetic Ingredient Review (CIR) Expert Panel.  The PMMA used in cosmetics is substantially the same as in medical devices.  The Panel concluded that these ingredients are safe as cosmetic ingredients in the practices of use and concentrations as described in this safety assessment.
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Amended safety assessment of Sesamum indicum (sesame) seed oil, hydrogenated sesame seed oil, Sesamum indicum (sesame) oil unsaponifiables, and sodium sesameseedate.
Int. J. Toxicol.
PUBLISHED: 07-21-2011
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Sesamum indicum (sesame) seed oil and related cosmetic ingredients are derived from Sesamum indicum. Sesamum indicum (sesame) seed oil, sesamum indicum (sesame) oil unsaponifiables, and hydrogenated sesame seed oil function as conditioning agents. Sodium sesameseedate functions as a cleansing agent, emulsifying agent, and a nonaqueous viscosity increasing agent. These ingredients are neither skin irritants, sensitizers, teratogens, nor carcinogens at exposures that would result from cosmetic use. Both animal and human data relevant to the cosmetic use of these ingredients were reviewed. The CIR Expert Panel concluded that these ingredients are safe in the present practices of use and concentration as described in this safety assessment.
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Discovery of 6-(2,4-difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (pamapimod) and 6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as orally
J. Med. Chem.
PUBLISHED: 03-04-2011
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The development of a new series of p38? inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38?, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.
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3-Amino-pyrazolo[3,4-d]pyrimidines as p38? kinase inhibitors: design and development to a highly selective lead.
Bioorg. Med. Chem. Lett.
PUBLISHED: 02-28-2011
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Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.
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Mass psychogenic illness: psychological predisposition and iatrogenic pseudo-vocal cord dysfunction and pseudo-reactive airways disease syndrome.
J Med Toxicol
PUBLISHED: 02-09-2011
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A multidisciplinary team assessed five patients who alleged chronic medically unexplained multiorgan system symptoms described by idiopathic environmental intolerance allegedly triggered by exposure to solvents used in membrane roofing repair work on an office building. The event precipitated an incident of mass psychogenic illness (MPI). Treating physicians diagnosed irritant-associated vocal cord dysfunction (IVCD) and reactive airways disease syndrome (RADS) resulting from exposure. The authors conducted medical, psychological, and industrial hygiene evaluations. Air monitoring data for total volatile organic compounds obtained during the 2-day exposure period, measurements of emissions during membrane roofing repair at a similar site, mathematical modeling of air contaminant concentrations, and injection of tracer gas into the incident building revealed exposure levels well below those doses anticipated to cause clinical symptoms. There was no objective medical evidence validating symptoms. Review of the medical records indicated that the video laryngoscopy data, pulmonary function tests, and medical examinations relied upon by the treating physicians were inconsistent with published criteria for IVCD and RADS. Psychological evaluation identified defensiveness and self-serving misrepresentations of exaggerated health concerns associated with somatization and malingering. Each case had personality traits associated with at least one personality disorder. Social histories identified premorbid life events and stressors associated with distress. This is the first study to assess psychological predisposition, social interaction among the plaintiffs, and iatrogenic reinforcement of beliefs by diagnoses of pseudo-disorders associated with patient misrepresentation of exaggerated health concerns in an incident of MPI.
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Isoforms of the heteropteran Nezara viridula ecdysone receptor: protein characterisation, RH5992 insecticide binding and homology modelling.
Pest Manag. Sci.
PUBLISHED: 02-01-2011
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Certain bisacylhydrazine compounds such as tebufenozide (RH5992) have been shown to act as order-specific insecticides. Their compatibility with predatory Heteroptera, which are used as biological control agents, has also been demonstrated. However, the molecular mode of action of these ecdysone agonists has not been explored in a heteropteran, much less one that is a significant agricultural pest, such as Nezara viridula.
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Amended safety assessment of dodecylbenzenesulfonate, decylbenzenesulfonate, and tridecylbenzenesulfonate salts as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 12-18-2010
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Sodium dodecylbenzenesulfonate is one of a group of salts of alkylbenzene sulfonates used in cosmetics as surfactant-cleansing agents. Sodium dodecylbenzenesulfonate is soluble in water and partially soluble in alcohol, with dermal absorption dependent on pH. Dodecylbenzenesulfonate salts are not toxic in single-dose oral and dermal animal tests, and no systemic toxicities were observed in repeat-dose dermal animal studies. In dermal animal studies, no evidence of reproductive or developmental toxicity was reported. At 15% concentrations, sodium dodecylbenzenesulfonate was severely irritating to rabbit skin. The Cosmetic Ingredient Review Expert Panel concluded that the irritant properties of these ingredients are similar to those of other detergents, with severity dependent on concentration and pH. Products containing these ingredients should be formulated to ensure that the irritancy potential is minimized.
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Final amended safety assessment of hydroquinone as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 12-18-2010
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Hydroquinone is an aromatic compound that functions in cosmetics as an antioxidant, fragrance, reducing agent, or polymerization inhibitor. Hydroquinone is also used as a skin bleaching agent. Safety and toxicity information indicate that hydroquinone is dermally absorbed in humans from both aqueous and alcoholic formulations and is excreted mainly as the glucuronide or sulfate conjugates. Hydroquinone is associated with altered immune function in vitro and in vivo in animals and an increased incidence of renal tubule cell tumors and leukemia in F344 rats, but the relevance to humans is uncertain. Quantitatively, however, the use of hydroquinone in cosmetics is unlikely to result in renal neoplasia through this mode of action. Thus, hydroquinone is safe at concentrations of ?1% in hair dyes and is safe for use in nail adhesives. Hydroquinone should not be used in other leave-on cosmetics.
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Final report of the safety assessment of Kojic acid as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 12-18-2010
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Kojic acid functions as an antioxidant in cosmetic products. Kojic acid was not a toxicant in acute, chronic, reproductive, and genotoxicity studies. While some animal data suggested tumor promotion and weak carcinogenicity, kojic acid is slowly absorbed into the circulation from human skin and likely would not reach the threshold at which these effects were seen. The available human sensitization data supported the safety of kojic acid at a use concentration of 2% in leave-on cosmetics. Kojic acid depigmented black guinea pig skin at a concentration of 4%, but this effect was not seen at 1%. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that the 2 end points of concern, dermal sensitization and skin lightening, would not be seen at use concentrations below 1%; therefore, this ingredient is safe for use in cosmetic products up to that level.
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Final report of the Cosmetic Ingredient Review Expert Panel amended safety assessment of Calendula officinalis-derived cosmetic ingredients.
Int. J. Toxicol.
PUBLISHED: 12-18-2010
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Calendula officinalis extract, C officinalis flower, C officinalis flower extract, C officinalis flower oil, and C officinalis seed oil are cosmetic ingredients derived from C officinalis. These ingredients may contain minerals, carbohydrates, lipids, phenolic acids, flavonoids, tannins, coumarins, sterols and steroids, monoterpenes, sesquiterpenes, triterpenes, tocopherols, quinones, amino acids, and resins. These ingredients were not significantly toxic in single-dose oral studies using animals. The absence of reproductive/developmental toxicity was inferred from repeat-dose studies of coriander oil, with a similar composition. Overall, these ingredients were not genotoxic. They also were not irritating, sensitizing, or photosensitizing in animal or clinical tests but may be mild ocular irritants. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that these ingredients are safe for use in cosmetics in the practices of use and concentration given in this amended safety assessment.
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Discovery of novel GSK-3? inhibitors with potent in vitro and in vivo activities and excellent brain permeability using combined ligand- and structure-based virtual screening.
J. Med. Chem.
PUBLISHED: 11-17-2010
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Dysregulation of glycogen synthase kinase (GSK-3?) is implicated in the pathophysiology of many diseases, including type-2 diabetes, stroke, Alzheimers, and others. A multistage virtual screening strategy designed so as to overcome known caveats arising from the considerable flexibility of GSK-3? yielded, from among compounds in our in-house database and two commercial databases, new GSK-3? inhibitors with novel scaffold structures. The two most potent and selective validated hits, a 2-anilino-5-phenyl-1,3,4-oxadiazole (24) and a phenylmethylene hydantoin (28), both exhibited nanomolar affinity and selectivity over CDK2 and were potent enough for direct in vivo validation. Both were able to cause significant increases in liver glycogen accumulation in dose-dependent fashion. One also exhibited excellent blood-brain barrier permeability, the other adequate for a lead compound. Analogues of the oxadiazole 24 were synthesized to experimentally corroborate or rule out ligand-bound structures arising from docking studies. SAR results supported one docking study among a number of alternatives.
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An ecdysone receptor from the pentatomomorphan, Nezara viridula, shows similar affinities for moulting hormones makisterone A and 20-hydroxyecdysone.
Insect Biochem. Mol. Biol.
PUBLISHED: 08-11-2010
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It has been suggested that Pentatomomorpha utilise the C(28) ecdysteroid, makisterone A (MakA), as the major moulting hormone rather than the more common C(27) hormone, 20-hydroxyecdsyone (20E). The present study is the first to examine this postulate at the level of the ecdysone receptor protein, a heterodimer of nuclear receptors EcR and USP. cDNAs encoding two alternatively spliced isoforms of EcR and a single USP were isolated from a high-quality cDNA library prepared from a representative pentatomomorphan, Nezara viridula (Nv). NvEcR and NvUSP were found to group phylogenetically with heteropteran and other insect EcRs and USP/RXRs, respectively. Sequence comparison and phylogenetic analysis of these proteins found them to be distinct from those belonging to other hemipteran ecdysone receptors characterised to date. Co-expression of the His(6)-tagged ligand binding regions (LBRs) of the two NvEcR variants with the FLAG-tagged LBR of NvUSP was achieved in insect cells employing appropriately constructed baculoviruses. The corresponding heterodimers, designated NvE10 and NvE11, were purified by affinity chromatography utilising the His(6) tags on their NvEcR subunits. The heterodimers displayed nanomolar affinity for [(3)H]ponasterone A (K(d) = 6.8-7.5 nM), characteristic of ecdysone receptors. MakA has a similar affinity to 20E for both NvE10 and NvE11, consistent with MakA being a major moulting hormone in N. viridula.
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Final report of the amended safety assessment of myristic acid and its salts and esters as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 07-17-2010
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This report addresses the safety of the inorganic salts and esters of various fatty alcohols of myristic acid. Most of the esters are used as skin conditioning agents in many types of cosmetics in a range of concentrations. Myristate esters are readily hydrolyzed to the corresponding alcohols and acids, which are then further metabolized. Myristate salts readily dissociate in any likely cosmetic formulation. The Cosmetic Ingredient Review (CIR) Panel recognized that much of the data supporting the ingredients in this group were previously reviewed in safety assessments for related ingredients. Where specific data did not exist, the Panel considered structure-activity relationships in determining the safety of these ingredients as used in cosmetics. The Panel determined that myristic acid and its salts and esters are safe as cosmetic ingredients in the current practices of use and concentration.
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Final report of the amended safety assessment of sodium laureth sulfate and related salts of sulfated ethoxylated alcohols.
Int. J. Toxicol.
PUBLISHED: 07-17-2010
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Sodium laureth sulfate is a member of a group of salts of sulfated ethoxylated alcohols, the safety of which was evaluated by the Cosmetic Ingredient Review (CIR) Expert Panel for use in cosmetics. Sodium and ammonium laureth sulfate have not evoked adverse responses in any toxicological testing. Sodium laureth sulfate was demonstrated to be a dermal and ocular irritant but not a sensitizer. The Expert Panel recognized that there are data gaps regarding use and concentration of these ingredients. However, the overall information available on the types of products in which these ingredients are used and at what concentrations indicates a pattern of use. The potential to produce irritation exists with these salts of sulfated ethoxylated alcohols, but in practice they are not regularly seen to be irritating because of the formulations in which they are used. These ingredients should be used only when they can be formulated to be nonirritating.
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Final safety assessment of thiodipropionic acid and its dialkyl esters as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 07-17-2010
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Dilauryl thiodipropionate (DLTDP), dicetyl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate, and ditridecyl thiodipropionate are dialkyl esters of their respective alcohols and thiodipropionic acid (TDPA) used in cosmetics. Ingested DLTDP was excreted in the urine as TDPA. Single-dose acute oral and parenteral studies and subchronic and chronic repeated dose oral studies did not suggest significant toxicity. Neither DLTDP nor TDPA was irritating to animal skin or eyes and they were not sensitizers. TDPA was neither a teratogen nor a reproductive toxicant. Genotoxicity studies were negative for TDPA and DLTDP. Clinical testing demonstrated some evidence of irritation but no sensitization or photosensitization. The Cosmetic Ingredient Review Expert Panel considered that the data from DLTDP reasonably may be extrapolated to the other dialkyl esters and concluded that these ingredients were safe for use in cosmetic products that are formulated to be nonirritating.
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Final report of the amended safety assessment of Quaternium-15 as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-08-2010
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Quaternium-15 is an antimicrobial agent used in cosmetics as a cosmetic preservative and antistatic agent. Little systemic toxicity was reported in most single-dose or repeated-dose animal studies. Quaternium-15 was an oral teratogen, but not a dermal teratogen, in rats at doses that exceeded the expected cumulative exposure from cosmetics. The frequency of sensitization increased in North America but not in Europe, where Quaternium-15 is used less often. In almost all animal and human studies, Quaternium-15 at 0.2% was not a sensitizer. The weight of evidence suggested that a 0.2% concentration is not a sensitizer and that cosmetic products containing Quaternium-15 up to that level are safe.
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Synthesis, binding and bioactivity of gamma-methylene gamma-lactam ecdysone receptor ligands: advantages of QSAR models for flexible receptors.
Bioorg. Med. Chem.
PUBLISHED: 04-16-2010
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Nuclear hormone receptors, such as the ecdysone receptor, often display a large amount of induced fit to ligands. The size and shape of the binding pocket in the EcR subunit changes markedly on ligand binding, making modelling methods such as docking extremely challenging. It is, however, possible to generate excellent 3D QSAR models for a given type of ligand, suggesting that the receptor adopts a relatively restricted number of binding site configurations or attractors. We describe the synthesis, in vitro binding and selected in vivo toxicity data for gamma-methylene gamma-lactams, a new class of high-affinity ligands for ecdysone receptors from Bovicola ovis (Phthiraptera) and Lucilia cuprina (Diptera). The results of a 3D QSAR study of the binding of methylene lactams to recombinant ecdysone receptor protein suggest that this class of ligands is indeed recognised by a single conformation of the EcR binding pocket.
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An ortholog of the ecdysone receptor protein (EcR) from the parasitic nematode Haemonchus contortus.
Mol. Biochem. Parasitol.
PUBLISHED: 03-02-2010
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High concentrations (> or =4.2mM) of 20E inhibit the development of Haemonchus contortus eggs to the L3 larval stage. We report the cloning of cDNA encoding an EcR ortholog (HcEcR) from H. contortus mRNA expressed during L3. Phylogenetically, this and the putative EcR from Brugia malayi form a separate branch between arthropod EcRs and liver X receptors. Two isoforms of HcEcR differ in the inclusion/omission of a 3-residue segment in the A/B domain. Single nucleotide polymorphisms at 49 positions can be grouped into two major patterns in the A/BC segment and two in the DE/F segment. Some 35% of the highly conserved ecdysteroid-contacting residues in insect EcRs are also conserved in the HcEcR ligand binding domain, but it contains unusual residue choices at other ligand-contacting positions. Recombinant co-expression of HcEcR DE/F segments with a phthirapteran USP DE/F segment in insect cells resulted in stable proteins which did not heterodimerize or bind [(3)H]ponasterone A.
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Ten years of change to coral communities off Mona and Desecheo Islands, Puerto Rico, from disease and bleaching.
Dis. Aquat. Org.
PUBLISHED: 12-02-2009
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Remote reefs off southwest Puerto Rico have experienced recent losses in live coral cover of 30 to 80%, primarily due to the decline of Montastraea annularis and M. faveolata from disease and bleaching. These species were formerly the largest, oldest, and most abundant corals on these reefs, constituting over 65% of the living coral cover and 40 to 80% of the total number of colonies. From 1998 to 2001, outbreaks of yellow band disease (YBD) and white plague (WP) affected 30 to 60% of the M. annularis (complex) colonies. Disease prevalence declined beginning in 2002, and then increased immediately following the 2005 mass bleaching event. Colonies of M. annularis (complex) have been reduced in abundance by 24 to 32%, and remaining colonies are missing more than half their tissue. Both M. annularis and M. faveolata have failed to recruit, resheeting has been minimal, and exposed skeletal surfaces are being colonized by macroalgae, bioeroding sponges, and hydrozoans. Other scleractinian corals were smaller in size (mean = 28 cm diameter) and exhibited lower levels of partial mortality; these taxa were affected to a lesser extent by coral diseases and bleaching-associated tissue loss over the last decade. The numbers of small colonies (1 to 9 cm) of these species identified since 2005 also exceeded numbers of larger colonies that died. These reefs appear to be exhibiting shifts in species assemblages, with replacement of M. annularis (complex) by shorter-lived brooding species and other massive and plating corals (Agaricia, Porites, Meandrina, Eusmilia, Diploria, and Siderastrea spp.). To avoid a catastrophic and permanent loss of the dominant, slow-growing reef-building corals, the causes and effects of diseases need to be better understood, and possible control mechanisms must be developed. In particular, steps must be taken to mitigate environmental and anthropogenic stressors that increase the spread and severity of disease.
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Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide.
Biochem. Pharmacol.
PUBLISHED: 07-10-2009
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One of the factors affecting the pharmacokinetics (PK) of a drug during pregnancy is the activity of hepatic and placental metabolizing enzymes. Recently, we reported on the biotransformation of glyburide by human hepatic and placental microsomes to six metabolites that are structurally identical between the two tissues. Two of the metabolites, 4-trans-(M1) and 3-cis-hydroxycyclohexyl glyburide (M2b), were previously identified in plasma and urine of patients treated with glyburide and are pharmacologically active. The aim of this investigation was to identify the major human hepatic and placental CYP450 isozymes responsible for the formation of each metabolite of glyburide. This was achieved by the use of chemical inhibitors selective for individual CYP isozymes and antibodies raised against them. The identification was confirmed by the kinetic constants for the biotransformation of glyburide by cDNA-expressed enzymes. The data revealed that the major hepatic isozymes responsible for the formation of each metabolite are as follows: CYP3A4 (ethylene-hydroxylated glyburide (M5), 3-trans-(M3) and 2-trans-(M4) cyclohexyl glyburide); CYP2C9 (M1, M2a (4-cis-) and M2b); CYP2C8 (M1 and M2b); and CYP2C19 (M2a). Human placental microsomal CYP19/aromatase was the major isozyme responsible for the biotransformation of glyburide to predominantly M5. The formation of significant amounts of M5 by CYP19 in the placenta could render this metabolite more accessible to the fetal circulation. The multiplicity of enzymes biotransforming glyburide and the metabolites formed underscores the potential for its drug interactions in vivo.
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The kinase activities of interleukin-1 receptor associated kinase (IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human cells.
Mol. Immunol.
PUBLISHED: 01-31-2009
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IRAK-1 and IRAK-4 are protein kinases that mediate signaling by Toll/IL1/Plant R (TIR) domain-containing receptors including the IL-1, IL-18, and Toll-like receptors (TLRs). Although well studied in mouse systems, the mechanism by which they function in human systems is less clear. To extend our knowledge of how these proteins regulate inflammatory signaling in human cells, we genetically and pharmacologically manipulated IRAK-1 and IRAK-4 kinase activities in vitro. Ablation of IRAK-4 expression in human umbilical vein endothelial cells (HUVEC) with siRNA suppressed IL-1beta induced IL-6 and IL-8 production whereas IRAK-1 siRNA suppressed TNFalpha induced but not IL-1beta induced cytokine production. Complementation of IRAK-4-depleted cells with a kinase-inactive allele restored IL-1beta induced cytokine gene expression suggesting that the IRAK-4 kinase activity is dispensable relative to its scaffolding function. Consistent with this finding, an IRAK-4 selective kinase inhibitor (RO6245) that inhibited IRAK-1 degradation failed to block IL-1beta induced cytokine production. In contrast, an inhibitor of both IRAK-1 and IRAK-4 (RO0884) reduced IL-1beta induced p38 MAP kinase, c-Jun N-terminal kinase activation, and IL-6 production in HUVEC. RO0884 also antagonized IL-1beta, TNFalpha, and TLR-mediated cytokine production in human fibroblast-like synoviocytes and peripheral blood mononuclear cells. Therefore in human cells the non-kinase functions of IRAK-4 are essential, whereas the kinase activity of IRAK-4 appears redundant with that of IRAK-1. Pharmacologic inhibition of both kinases appears necessary to block pro-inflammatory cytokine production.
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Safety assessment of alkyl benzoates as used in cosmetics.
Int. J. Toxicol.
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The functions of alkyl benzoates in cosmetics include fragrance ingredients, skin-conditioning agents--emollient, skin-conditioning agents--miscellaneous, preservatives, solvents, and plasticizers. The Cosmetic Ingredient Review Expert Panel reviewed the relevant animal and human data and noted gaps in the available safety data for some of the alkyl benzoates. Similar structure activity relationships, biologic functions, and cosmetic product usage allowed the available data of many of the alkyl benzoates to be extended to the entire group. Carcinogenicity data were not available, but available data indicated that these alkyl benzoate cosmetic ingredients are not genotoxic. Also benzoic acid and tested component alcohols were not reproductive or developmental toxicants, are not genotoxic in almost all assays, and are not carcinogenic. These ingredients were determined to be safe in the present practices of use and concentration.
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Safety assessment of trimoniums as used in cosmetics.
Int. J. Toxicol.
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Quaternary ammonium salts, including alkyl chain, alkanol, and polymer derivatives (trimoniums) are used in cosmetics mainly as surfactant-cleansing agents, hair-conditioning agents, and antistatic agents.  The Cosmetic Ingredient Review Expert Panel reviewed the relevant animal and human data and noted gaps in the available safety data for some of the trimomiums.  The available data on many of the trimoniums are sufficient, however, and similar structural activity relationships, functions in cosmetics, and cosmetic product usage supported extending these data to the entire group.  These ingredients were determined to be safe in the present practices of use and concentration when formulated to be nonirritating.
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Safety assessment of isoparaffins as used in cosmetics.
Int. J. Toxicol.
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The safety of isoparaffins as used in cosmetic products is reviewed in this safety assessment. These ingredients function mostly as solvents and also function as emollients in the 0001% to 90% concentration range. The Cosmetic Ingredient Review (CIR) Expert Panel has reviewed relevant animal and clinical data and concluded that these ingredients are safe in the present practices of use and concentration described in this safety assessment.
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Safety assessment of propylene glycol, tripropylene glycol, and PPGs as used in cosmetics.
Int. J. Toxicol.
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Propylene glycol is an aliphatic alcohol that functions as a skin conditioning agent, viscosity decreasing agent, solvent, and fragrance ingredient in cosmetics. Tripropylene glycol functions as a humectant, antioxidant, and emulsion stabilizer. Polypropylene glycols (PPGs), including PPG-3, PPG-7, PPG-9, PPG-12, PPG-13, PPG-15, PPG-16, PPG-17, PPG-20, PPG-26, PPG-30, PPG-33, PPG-34, PPG-51, PPG-52, and PPG-69, function primarily as skin conditioning agents, with some solvent use. The majority of the safety and toxicity information presented is for propylene glycol (PG). Propylene glycol is generally nontoxic and is noncarcinogenic. Clinical studies demonstrated an absence of dermal sensitization at use concentrations, although concerns about irritation remained. The CIR Expert Panel determined that the available information support the safety of tripropylene glycol as well as all the PPGs. The Expert Panel concluded that PG, tripropylene glycol, and PPGs ?3 are safe as used in cosmetic formulations when formulated to be nonirritating.
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Safety assessment of alkyl PEG ethers as used in cosmetics.
Int. J. Toxicol.
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The CIR Expert Panel assessed the safety of Alkyl PEG Ethers as used in cosmetics. These ingredients primarily function in cosmetics as surfactants, and some have additional functions as skin-conditioning agents, fragrance ingredients, and emulsion stabilizers. The Panel reviewed available relevant animal and clinical data, as well as information from previous CIR reports; when data were not available for individual ingredients, the Panel extrapolated from the existing data to support safety. The Panel concluded that the Alkyl PEG ethers are safe as used when formulated to be nonirritating, and the same applies to future alkyl PEG ether cosmetic ingredients that vary from those ingredients recited herein only by the number of ethylene glycol repeat units.
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Safety assessment of 1,2-glycols as used in cosmetics.
Int. J. Toxicol.
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Caprylyl glycol and related 1,2-glycols are used mostly as skin and hair conditioning agents and viscosity agents in cosmetic products, and caprylyl glycol and pentylene glycol also function as cosmetic preservatives. The Cosmetic Ingredient Review (CIR) Expert Panel noted that, while these ingredients are dermally absorbed, modeling data predicted decreased skin penetration of longer chain 1,2-glycols. Because the negative oral toxicity data on shorter chain 1,2-glycols and genotoxicity data support the safety of the 1,2-glycols reviewed in this safety assessment, the Panel concluded that these ingredients are safe in the present practices of use and concentration described in this safety assessment.
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Safety assessment of stearyl heptanoate and related stearyl alkanoates as used in cosmetics.
Int. J. Toxicol.
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Stearyl heptanoate is an ester of stearyl alcohol and heptanoic acid that functions in cosmetics as a skin conditioning agent and is in the general class of chemicals called stearyl alkanoates. Stearyl caprylate, stearyl palmitate, stearyl stearate, stearyl behenate, and stearyl olivate are stearyl alkanoates with similar chemical structures, toxicokinetics, and functions in cosmetics. These water-insoluble stearyl alkanoates, when metabolized, yield stearyl alcohol and a corresponding fatty acid. The available information supports the safety of all of the related stearyl alkanoates. The Expert Panel concluded that stearyl heptanoate, stearyl caprylate, stearyl palmitate, stearyl stearate, stearyl behenate, and stearyl olivate are safe in the present practices of use and concentration.
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Ecdysone receptors: from the Ashburner model to structural biology.
Annu. Rev. Entomol.
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In 1974, Ashburner and colleagues postulated a model to explain the control of the puffing sequence on Drosophila polytene chromosomes initiated by the molting hormone 20-hydroxyecdysone. This model inspired a generation of molecular biologists to clone and characterize elements of the model, thereby providing insights into the control of gene networks by steroids, diatomic gases, and other small molecules. It led to the first cloning of the EcR subunit of the heterodimeric EcR-USP ecdysone receptor. X-ray diffraction studies of the ligand-binding domain of the receptor are elucidating the specificity of receptor-ecdysteroid interactions, the selectivity of some environmentally friendly insecticides, the evolution of the EcR-USP heterodimer, and indeed Ashburners classical biochemical evidence for the central role of the ecdysone receptor in his model.
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Final report of the Cosmetic Ingredient Review Expert Panel on the safety assessment of cocamidopropyl betaine (CAPB).
Int. J. Toxicol.
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Cocamidopropyl betaine (CAPB) and related amidopropyl betaines are zwitterions used mainly as surfactants in cosmetics. These cosmetic ingredients are similar in their chemistry, in particular with respect to the presence of 3,3-dimethylamino-propylamine (DMAPA) and fatty acid amidopropyl dimethylamine (amidoamine) impurities, which are known as sensitizers. The CIR Expert Panel concluded that because these ingredients present no other significant toxicity, when formulated to be nonsensitizing (which may be based on a quantitative risk assessment), these ingredients are safe for use as cosmetic ingredients in the practices of use and concentration of this safety assessment.
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Final report of the Cosmetic Ingredient Review Expert Panel on the safety assessment of dicarboxylic acids, salts, and esters.
Int. J. Toxicol.
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The CIR Expert Panel assessed the safety of dicarboxylic acids and their salts and esters as used in cosmetics. Most dicarboxylic acids function in cosmetics as pH adjusters or fragrance ingredients, but the functions of most of the salts in cosmetics are not reported. Some of the esters function as skin conditioning or fragrance ingredients, plasticizers, solvents, or emollients. The Expert Panel noted gaps in the available safety data for some of the dicarboxylic acid and their salts and esters in this safety assessment. The available data on many of the ingredients are sufficient, however, and similar structural activity relationships, biologic functions, and cosmetic product usage suggest that the available data may be extrapolated to support the safety of the entire group. The Panel concluded that the ingredients named in this report are safe in the present practices of use and concentration.
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Final report of the Cosmetic Ingredient Review Expert Panel on the safety assessment of methyl acetate.
Int. J. Toxicol.
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Alkyl acetates, as well as acetic acid and acetate salts, are widely used cosmetic ingredients, with a wide range of functions as fragrances, solvents, or skin-conditioning agents, depending on the specific ingredient. Available data on alkyl acetates, and acetic acid and the alcohol to which they could be metabolized, were considered adequate to support the safety of the entire group in the present practices of use and concentration in cosmetics.
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RN486, a selective Brutons tyrosine kinase inhibitor, abrogates immune hypersensitivity responses and arthritis in rodents.
J. Pharmacol. Exp. Ther.
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Genetic mutation and pharmacological inhibition of Brutons tyrosine kinase (Btk) both have been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor, 6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one (RN486), in vitro and in rodent models of immune hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell types, blocking Fc? receptor cross-linking-induced degranulation in mast cells (IC(50) = 2.9 nM), Fc? receptor engagement-mediated tumor necrosis factor ? production in monocytes (IC(50) = 7.0 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC(50) = 21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing type I and type III hypersensitivity responses. More importantly, RN486 produced robust anti-inflammatory and bone-protective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small-molecule disease-modifying drugs for RA and potentially other autoimmune diseases.
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