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Selected AbstractsPharmacokinetics of dipeptidylpeptidase-4 inhibitorsDIABETES OBESITY & METABOLISM, Issue 8 2010A. J. Scheen Type 2 diabetes (T2DM) is a complex disease combining defects in insulin secretion and insulin action. New compounds have been developed for improving glucose-induced insulin secretion and glucose control, without inducing hypoglycaemia or weight gain. Dipeptidylpeptidase-4 (DPP-4) inhibitors are new oral glucose-lowering agents, so-called incretin enhancers, which may be used as monotherapy or in combination with other antidiabetic compounds. Sitagliptin, vildaglipin and saxagliptin are already on the market in many countries, either as single agents or in fixed-dose combined formulations with metformin. Other DPP-4 inhibitors, such as alogliptin and linagliptin, are currently in late phase of development. The present paper summarizes and compares the main pharmacokinetics (PK) properties, that is, absorption, distribution, metabolism and elimination, of these five DPP-4 inhibitors. Available data were obtained in clinical trials performed in healthy young male subjects, patients with T2DM, and patients with either renal insufficiency or hepatic impairment. PK characteristics were generally similar in young healthy subjects and in middle-aged overweight patients with diabetes. All together gliptins have a good oral bioavailability which is not significantly influenced by food intake. PK/pharmacodynamics characteristics, that is, sufficiently prolonged half-life and sustained DPP-4 enzyme inactivation, generally allow one single oral administration per day for the management of T2DM; the only exception is vildagliptin for which a twice-daily administration is recommended because of a shorter half-life. DPP-4 inhibitors are in general not substrates for cytochrome P450 (except saxagliptin that is metabolized via CYP 3A4/A5) and do not act as inducers or inhibitors of this system. Several metabolites have been documented but most of them are inactive; however, the main metabolite of saxagliptin also exerts a significant DPP-4 inhibition and is half as potent as the parent compound. Renal excretion is the most important elimination pathway, except for linagliptin whose metabolism in the liver appears to be predominant. PK properties of gliptins, combined with their good safety profile, explain why no dose adjustment is necessary in elderly patients or in patients with mild to moderate hepatic impairment. As far as patients with renal impairment are concerned, significant increases in drug exposure for sitagliptin and saxagliptin have been reported so that appropriate reductions in daily dosages are recommended according to estimated glomerular filtration rate. The PK characteristics of DPP-4 inhibitors suggest that these compounds are not exposed to a high risk of drug,drug interactions. However, the daily dose of saxagliptin should be reduced when coadministered with potent CYP 3A4 inhibitors. In conclusion, besides their pharmacodynamic properties leading to effective glucose-lowering effect without inducing hypoglycaemia or weight gain, DPP-4 inhibitors show favourable PK properties, which contribute to a good efficacy/safety ratio for the management of T2DM in clinical practice. [source] Antidepressants and their metabolites in municipal wastewater, and downstream exposure in an urban watershedENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2010Chris D. Metcalfe Abstract Antidepressants are a widely prescribed group of pharmaceuticals that can be biotransformed in humans to biologically active metabolites. In the present study, the distribution of six antidepressants (venlafaxine, bupropion, fluoxetine, sertraline, citalopram, and paroxetine) and five of their metabolites was determined in a municipal wastewater treatment plant (WWTP) and at sites downstream of two WWTPs in the Grand River watershed in southern Ontario, Canada. Fathead minnows (Pimephales promelas) caged in the Grand River downstream of a WWTP were also evaluated for accumulated antidepressants. Finally, drinking water was analyzed from a treatment plant that takes its water from the Grand River 17 km downstream of a WWTP. In municipal wastewater, the antidepressant compounds present in the highest concentrations (i.e., >0.5 µg/L) were venlafaxine and its two demethylation products, O - and N -desmethyl venlafaxine. Removal rates of the target analytes in a WWTP were approximately 40%. These compounds persisted in river water samples collected at sites up to several kilometers downstream of discharges from WWTPs. Venlafaxine, citalopram, and sertraline, and demethylated metabolites were detected in fathead minnows caged 10 m below the discharge from a WWTP, but concentrations were all <7 µg/kg wet weight. Venlafaxine and bupropion were detected at very low (<0.005 µg/L) concentrations in untreated drinking water, but these compounds were not detected in treated drinking water. The present study illustrates that data are needed on the distribution in the aquatic environment of both the parent compound and the biologically active metabolites of pharmaceuticals. Environ. Toxicol. Chem. 2010;29:79,89. © 2009 SETAC [source] Reproductive health of bass in the Potomac, USA, drainage: Part 2.ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 5 2009Seasonal occurrence of persistent, emerging organic contaminants Abstract The seasonal occurrence of organic contaminants, many of which are potential endocrine disruptors, entering the Potomac River, USA, watershed was investigated using a two-pronged approach during the fall of 2005 and spring of 2006. Passive samplers (semipermeable membrane device and polar organic chemical integrative sampler [POCIS]) were deployed in tandem at sites above and below wastewater treatment plant discharges within the watershed. Analysis of the samplers resulted in detection of 84 of 138 targeted chemicals. The agricultural pesticides atrazine and metolachlor had the greatest seasonal changes in water concentrations, with a 3.1- to 91-fold increase in the spring compared with the level in the previous fall. Coinciding with the elevated concentrations of atrazine in the spring were increasing concentrations of the atrazine degradation products desethylatrazine and desisopropylatrazine in the fall following spring and summer application of the parent compound. Other targeted chemicals (organochlorine pesticides, polycyclic aromatic hydrocarbons, and organic wastewater chemicals) did not indicate seasonal changes in occurrence or concentration; however, the overall concentrations and number of chemicals present were greater at the sites downstream of wastewater treatment plant discharges. Several fragrances and flame retardants were identified in these downstream sites, which are characteristic of wastewater effluent and human activities. The bioluminescent yeast estrogen screen in vitro assay of the POCIS extracts indicated the presence of chemicals that were capable of producing an estrogenic response at all sampling sites. [source] Whole sediment toxicity identification evaluation tools for pyrethroid insecticides: III.ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2009Temperature manipulation Abstract Since the toxicity of pyrethroid insecticides is known to increase at low temperatures, the use of temperature manipulation was explored as a whole-sediment toxicity identification evaluation (TIE) tool to help identify sediment samples in which pyrethroid insecticides are responsible for observed toxicity. The amphipod Hyalella azteca is commonly used for toxicity testing of sediments at a 23°C test temperature. However, a temperature reduction to 18°C doubled the toxicity of pyrethroids, and a further reduction to 13°C tripled their toxicity. A similar response, though less dramatic, was found for 1,1-bis(p -chlorophenyl)-2,2,2-trichloroethane (DDT), and dissimilar temperature responses were seen for cadmium and the insecticide chlorpyrifos. Tests with field-collected sediments containing pyrethroids and/or chlorpyrifos showed the expected thermal dependency in nearly all instances. The inverse relationship between temperature and toxicity provides a simple approach to help establish when pyrethroids are the principal toxicant in a sediment sample that could be used as a supplemental tool in concert with chemical analysis or other TIE manipulations. The phenomenon appears to be, in part, a consequence of a reduced ability to biotransform the toxic parent compound at cooler temperatures. The strong dependence of pyrethroid toxicity on temperature has important ramifications for predicting their environmental effects, and the standard test temperature of 23°C dramatically underestimates risk to resident fauna during the cooler months. [source] Toxicological characterization of 2,4,6-trinitrotoluene, its transformation products, and two nitramine explosivesENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 6 2007Judith Neuwoehner Abstract The soil and groundwater of former ordnance plants and their dumping sites have often been highly contaminated with the explosive 2,4,6-trinitrotoluene (2,4,6-TNT) leading to a potential hazard for humans and the environment. Further hazards can arise from metabolites of transformation, by-products of the manufacturing process, or incomplete combustion. This work examines the toxicity of polar nitro compounds relative to their parent compound 2,4,6-TNT using four different ecotoxicological bioassays (algae growth inhibition test, daphnids immobilization test, luminescence inhibition test, and cell growth inhibition test), three genotoxicological assays (umu test, NM2009 test, and SOS Chromotest), and the Ames fluctuation test for detection of mutagenicity. For this study, substances typical for certain steps of degradation/transformation of 2,4,6-TNT were chosen for investigation. This work determines that the parent compounds 2,4,6-TNT and 1,3,5-trinitrobenzene are the most toxic substances followed by 3,5-dinitrophenol, 3,5-dinitroaniline and 4-amino-2-nitrotoluene. Less toxic are the direct degradation products of 2,4,6-TNT like 2,4-dinitrotoluene, 2,6-dinitrotoluene, 2-amino-4,6-dinitrotoluene, and 4-amino-2,6-dinitrotoluene. A weak toxic potential was observed for 2,4,6-trinitrobenzoic acid, 2,4-diamino-6-nitrotoluene, 2,4-dinitrotoluene-5-sulfonic acid, and 2,6-diamino-4-nitrotoluene. Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine and hexahydro-1,3,5-trinitro-1,3,5-triazine show no hint of acute toxicity. Based on the results of this study, we recommend expanding future monitoring programs of not only the parent substances but also potential metabolites based on conditions at the contaminated sites and to use bioassays as tools for estimating the toxicological potential directly by testing environmental samples. Site-specific protocols should be developed. If hazardous substances are found in relevant concentrations, action should be taken to prevent potential risks for humans and the environment. Analyses can then be used to prioritise reliable estimates of risk. [source] Toxicity and fate of two munitions constituents in spiked sediment exposures with the marine amphipod Eohaustorius estuariusENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2005Gunther Rosen Abstract The lethal toxicity of the explosive compounds 14C-labeled 2,4,6-trinitrotoluene (TNT) and nonradiolabeled hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) to the estuarine amphipod Eohaustorius estuarius was investigated in 10-d spiked sediment exposures. The 10-d median lethal concentration (LC50) was determined using the sum molar initial concentration of TNT, ami-nodinitrotoluenes (ADNTs), and diaminonitrotoluenes (DANTs), as determined by high-performance liquid chromatography (HPLC), and collectively referred to as HPLC-TNT*. Despite expectations of higher toxicity in sandy sediment (Yaquina Bay [YB], OR, USA) compared to relatively fine-grained sediment (San Diego Bay [SDB], CA, USA), LC50 values were similar: 159 and 125 ,mol/kg, for YB and SDB sediments, respectively. When expressed as the sum of TNT and all its degradation products (14C-TNT*), LC50s were approximately two times the corresponding LC50s determined by HPLC. The HPLC-TNT* fraction likely corresponds to the most bioavailable and toxic transformation products. The concentrations of 14C-TNT* in tissues were substantially higher than those for HPLC-TNT*, suggesting that compounds other than TNT and its major aminated transformation products were prevalent. Critical body residues were similar for exposures to SDB (11.7 ,mol/kg) and YB sediments (39.4 ,mol/kg), despite marked differences in the nature of compounds available for uptake in the exposure media. The critical body residues for E. estuarius are lower than those reported for other aquatic invertebrates (83,172 ,mol/kg). Unlike observations for TNT, RDX was only loosely associated with SDB sediment, with near complete recovery of the parent compound by chemical analysis. Exposure to RDX did not result in significant mortality even at the highest measured sediment concentration of 10,800 ,mol/kg dry weight, nor tissue concentrations as high as 96 ,mol/kg wet weight. The lack of RDX lethal effects in this study is consistent with results reported for other invertebrate species. [source] Aqueous photolysis of 8:2 fluorotelomer alcoholENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 8 2005Suzanne A. Gauthier Abstract The 8:2 fluorotelomer alcohol (8:2 FTOH) was photodegraded in aqueous hydrogen peroxide solutions, synthetic field water (SFW) systems, and Lake Ontario (Canada) water samples. It was found to undergo indirect photolysis, with the data suggesting that the hydroxyl radical was the main degradation agent and that nitrate promoted photolysis whereas dissolved organic carbon inhibited it. The half-lives of 8:2 FTOH were 0.83 ± 0.20 h (10 mM H2O2), 38.0 ± 6.0 h (100 ,M H2O2), 30.5 ± 8.0 to 163.1 ± 3.0 h (SFW systems), and 93.2 ± 10.0 h (Lake Ontario). No significant loss of the parent compound by direct photolysis could be observed. The major monitored products were the 8:2 fluorotelomer aldehyde, the 8:2 fluorotelomer acid (8:2 FTCA), and perfluorooctanoate (PFOA); the minor monitored products were the 8:2 fluorotelomer unsaturated acid (8:2 FTUCA) and perfluorononanoate (PFNA). The intermediates, 8:2 FTCA and 8:2 FTUCA, were photodegraded to verify the degradation pathway, and a mechanism for the photolysis was proposed whereby the end products of the photolysis pathway were PFOA (major) and PFNA (minor). [source] Effect of byproducts from the ozonation of pyrene: Biphenyl-2,2,,6,6,-tetracarbaldehyde and biphenyl-2,2,,6,6,-tetracarboxylic acid on gap junction intercellular communication and neutrophil functionENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2005Stephanie L. Luster-Teasley Abstract In this study, biphenyl-2,2,,6,6,-tetracarbaldehyde, an initial by product formed from the ozonation of pyrene, and biphenyl-2,2,,6,6,-tetracarboxylic acid, a subsequent pyrene ozonation byproduct, were evaluated using two toxicology assays to compare the toxicity of ozonation byproducts with that of the parent compound. The first assay measured the potential for the compounds to block gap junctional intercellular communication (GJIC) using the scrape loading/dye transfer technique in normal WB-344 rat liver epithelial cells. The second assay evaluated the ability of the compounds to affect neutrophil function by measuring the production of superoxide in a human cell line (HL-60). Pyrene significantly blocked intercellular communication (f= 0.2,0.5) at 40 ,M and complete inhibition of communication (f < 0.2) occurred at 50 ,M. Gap junctional intercellular communication in cells exposed to biphenyl-2,2,,6,6,-tetracarbaldehyde reached f < 0.5 at a concentration of 15 ,M. At concentrations greater than 20 ,M, biphenyl-2,2,,6,6,-tetracarbaldehyde was cytotoxic and the inhibition of GJIC was caused by cell death. Biphenyl-2,2,,6,6,-tetracarboxylic acid was neither cytotoxic nor inhibitory to GJIC at the concentrations tested (10,500 ,M). Exposure to biphenyl-2,2,,6,6,-tetracarbaldehyde resulted in a concentration-dependent decrease in phorbol 12-myristate 13-acetate,stimulated O12 production. Neither exposure to pyrene nor biphenyl-2,2,,6,6,-tetracarboxylic acid caused a significant toxic effect on neutrophil function. [source] Fate and stability of 14C-labeled 2,4,6-trinitrotoluene in contaminated soil following microbial bioremediation processesENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2004Martin Weiß Abstract Biological treatment of 2,4,6-trinitrotoluene (TNT) in soil rarely results in complete mineralization of the parent compound. More often, the largest proportion of the TNT carbon is incorporated into the soil organic matrix. Therefore, we evaluated the stability of nonextractable residues from various bioremediation processes of 14C-TNT in soils. The extractable amounts of the residual radioactivity varied between 7 and 33% and thus the nonextractable amount between 93 and 67% (3,15% in fulvic acids, 26,46% in humic acids, and 27,44% in the humin fraction). The residue-containing soils were analyzed for the release of radioactivity after treatment by physical (freeze and thaw, grinding of soil, and steam extraction), chemical (acid rain and addition of metal complexing agent), and biological methods (addition of compost, white rot fungi, radical-generating enzymes, and germination of plants). Freeze and thaw treatment and grinding of the soil did not alter the partitioning of the label significantly. Steam extraction and acid rain extraction increased the water extractability to 11 to 29% and to 51.6% in the native TNT-contaminated soil. The addition of ethylenediamine-tetraacetate (EDTA) increased the extractability from 7 to 12%. After biological treatment, only slightly increased extractability (<<10%) was observed. No increase of extractable TNT or known metabolites was observed with any of the treatments. Thus, under the treatment conditions applied in this study, the residues formed during microbial transformation of TNT may be biogenic residues with low mobilization potential and low hazardous impact. [source] Fate and effects of triclosan in activated sludgeENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2002Thomas W. Federle Abstract Triclosan (TCS; 5-chloro-2-[2,4-dichloro-phenoxy]-phenol) is a widely used antimicrobial agent. To understand its fate during sewage treatment, the biodegradation and removal of TCS were determined in activated sludge. In addition, the effects of TCS on treatment processes were assessed. Fate was determined by examining the biodegradation and removal of TCS radiolabeled with 14C in the 2,4-dichlorphenoxy ring in laboratory batch mineralization experiments and bench-top continuous activated-sludge (CAS) systems. In batch experiments with unacclimated sludge, TCS was mineralized to 14CO2, but the total yield varied as a function of test concentration. Systems that were redosed with TCS exhibited more extensive and faster mineralization, indicating that adaptation was a critical factor determining the rate and extent of biodegradation. In a CAS study in which the influent level of TCS was incrementally increased from 40 ,g/L to 2,000 ,g/L, removal of the parent compound exceeded 98.5% and removal of total radioactivity (parent and metabolites) exceeded 85%. Between 1.5 and 4.5% of TCS in the influent was sorbed to the wasted solids, whereas >94% underwent primary biodegradation and 81 to 92% was mineralized to CO2 or incorporated in biomass. Increasing levels of TCS in the influent had no major adverse effects on any wastewater treatment process, including chemical oxygen demand, biological oxygen demand, and ammonia removal. In a subsequent experiment, a CAS system, acclimated to TCS at 35 ,g/L, received two separate 4-h shock loads of 750 ,g/L TCS. Neither removal of TCS nor treatment processes exhibited major adverse effects. An additional CAS study was conducted to examine the removal of a low level (10 ,g/L) of TCS. Removal of parent equaled 94.7%, and biodegradation remained the dominant removal mechanism. A subsequent series of CAS experiments examined removal at four influent concentrations (7.5, 11, 20, and 50 ,g/L) of TCS and demonstrated that removal of parent ranged from 98.2 to 99.3% and was independent of concentration. Although TCS removal across all experiments appeared unrelated to influent concentration, removal was significantly correlated (r2 = 0.87) with chemical oxygen demand removal, indicating that TCS removal was related to overall treatment efficiency of specific CAS units. In conclusion, the experiments show that TCS is extensively biodegraded and removed in activated-sludge systems and is unlikely to upset sewage treatment processes at levels expected in household and manufacturing wastewaters. [source] Quantification of in vivo biotransformation of the anionic surfactant C12 -2-linear alkylbenzene sulfonate in fathead minnowsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2000Johannes Tolls Abstract Linear alkylbenzene sulfonate (LAS) is a major surfactant in household detergents and enters the environment via the wastewater. Aquatic organisms are thus exposed to LAS and can bioaccumulate this compound. Even though the extent of bio-accumulation is determined by the organisms' capability of metabolizing LAS, little is known about metabolism of LAS in small aquatic organisms. In the present investigation, we present a novel approach to quantify in vivo biotransformation. Fish (fathead minnows [Pimephales promelas]) were exposed to the LAS constituent 2- n -(p -sulfophenyl)-dodecane (C12 -2-LAS). The parent surfactant and its biotransformation product 3- n -(p -sulfophenyl)-butyric acid (C4 -3-SPC) were determined in fish tissue. On the average, the concentration of C4 -3-SPC in fish was 70 to 80% of that of C12 -2-LAS. The first-order one-compartment model of bioconcentration was extended to include biotransformation as an explicit process. Analysis of the C4 -3-SPC/C12 -2-LASconcentration ratio in fish allowed estimating a rate constant for in vivo biotransformation of C12 -2-LAS in fathead minnows. With the estimates of the biotransformation rate constant (kBT,LAS) ranging between 0.31 and 0.72/d, biotransformation contributes to more than 40% of the elimination of C12 -2-LAS in fathead minnows. This indicates that biotransformation is a significant process in reducing the bioaccumulation potential of LAS. Moreover, the present investigation demonstrates that the combination of measurements of parent compound and metabolite with an extended bioaccumulation model is a viable approach for quantification of biotransformation in small aquatic test animals. [source] Impact of inter-individual differences in drug metabolism and pharmacokinetics on safety evaluationFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2004J.L.C.M. Dorne Abstract Safety evaluation aims to assess the dose,response relationship to determine a dose/level of exposure for food contaminants below which no deleterious effect is measurable that is ,without appreciable health risk' when consumed daily over a lifetime. These safe levels, such as the acceptable daily intake (ADI) have been derived from animal studies using surrogates for the threshold such as the no-observed-adverse-effect-level (NOAEL). The extrapolation from the NOAEL to the human safe intake uses a 100-fold uncertainty factor, defined as the product of two 10-fold factors allowing for human variability and interspecies differences. The 10-fold factor for human variability has been further subdivided into two factors of 100.5 (3.16) to cover toxicokinetics and toxicodynamics and this subdivsion allows for the replacement of an uncertainty factor with a chemical-specific adjustment factor (CSAF) when compound-specific data are available. Recently, an analysis of human variability in pharmacokinetics for phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferase, glucuronidation, glycine conjugation, sulphation) and renal excretion was used to derive pathway-related uncertainty factors in subgroups of the human population (healthy adults, effects of ethnicity and age). Overall, the pathway-related uncertainty factors (99th centile) were above the toxicokinetic uncertainty factor for healthy adults exposed to xenobiotics handled by polymorphic metabolic pathways (and assuming the parent compound was the proximate toxicant) such as CYP2D6 poor metabolizers (26), CYP2C19 poor metabolizers (52) and NAT-2 slow acetylators (5.2). Neonates were the most susceptible subgroup of the population for pathways with available data [CYP1A2 and glucuronidation (12), CYP3A4 (14), glycine conjugation (28)]. Data for polymorphic pathways were not available in neonates but uncertainty factors of up to 45 and 9 would allow for the variability observed in children for CYP2D6 and CYP2C19 metabolism, respectively. This review presents an overview on the history of uncertainty factors, the main conclusions drawn from the analysis of inter-individual differences in metabolism and pharmacokinetics, the development of pathway-related uncertainty factors and their use in chemical risk assessment. [source] Synthesis and Qualitative Olfactory Evaluation of Benzodioxepine AnaloguesHELVETICA CHIMICA ACTA, Issue 5 2007Britta Drevermann Abstract Marine fragrances, particularly Calone 1951® (=7-methyl-2H -1,5-benzodioxepin-3(4H)-one; 1) has carved a minor but distinct niche in the broad field of fragrance chemistry. By focusing on the polar structure fragment of the benzodioxepinone parent compound, we set out to determine the molecular influence on the dominant marine note attributed to the Calone 1951® structure. A selection of one-step modifications of the ketone 1 resulted in a range of odor-active conformers with diverse olfactory attributes. The synthesis of a range of benzodioxepine analogues, i.e., of 3,11, is presented alongside olfactory evaluation (Tables 2 and 3). Removal of the carbonyl group of 1 and increasing the size of the aliphatic ring portion (see 6 and 7) introduced sweetness and a predominant loss of the marine character. [source] Substituted 1,3,2,4-benzodithiadiazines: Novel derivatives, by-products, and intermediates,HETEROATOM CHEMISTRY, Issue 7 2001Alexander Yu. The synthesis of the title compounds 1 by 1:1 condensation of ArNSNSiMe3 2 with SCl2 followed by intramolecular ortho-cyclization of each [ArNSNSCl] intermediate is complicated by further reaction of 1 with SCl2 to give Herz salts 3. With the 2:SCl2 ratio of 2:1, the formation of by-products 3 is reduced and novel compounds 1 are accessible. With ortho-I containing starting material 2j, the parent compound 1s is obtained as the result of an unexpected I, not H, substitution. The rate of the 1 + SCl2 reaction depends upon a substituent's position, and the minor 8-R isomers 1l,p (R = Br, I) are isolated for the first time from mixtures with the major 6-R isomers due to reduced reactivity toward SCl2. The synthesized compounds 1,3 are characterized by multinuclear (including nitrogen) NMR and X-ray crystallography. According to the X-ray diffraction data, 1j (6-Br) and 1k (7-Br) derivatives are planar, whereas 1i (5-Br) and 1l (8-Br) are bent along the S1···N4 line by ,5° and ,4°, respectively, and the 1r (7-OCH3) derivative is planar in contrast to the known 5-OCH3 isomer, which possesses a significantly folded heterocycle. The distortion of the planar geometry of some compounds 1 is interpreted in terms of a pseudo-Jahn-Teller effect as the result of ,-highest occupied molecular orbital (HOMO) ,*-(LUMO) lowest unoccupied molecular orbital + 1 mixing in a planar conformation. The 2p compound is the first structurally defined Ar,N = S = N,SiMe3 azathiene. The compound Ar,N = S = N,S,NH-Ar 6 modeling the aforementioned intermediate has been isolated and structurally characterized. We describe the attempts to synthesize compounds 1 from 2-aminobenzenethiols and (SN)4 and from salts 3 and Me3SiN3, and we discuss the reaction pathways. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:563,576, 2001 [source] Dyspnoea after antiplatelet agents: the AZD6140 controversyINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 3 2007V. L. Serebruany Summary Recent randomised studies suggest that experimental oral reversible platelet P2Y12 receptor inhibitor, AZD6140, causes dyspnoea. This also raises similar concerns about the parent compound, and another adenosine triphosphate (ATP) analogue (AR-69931MX or cangrelor), which is currently in Phase 3 trial in patients undergoing coronary interventions. We analysed package inserts, and available clinical trials safety data for antiplatelet agents with regard to the incidence of dyspnoea. We found that dyspnoea is a very rare complication of the presently approved platelet inhibitors, mostly caused by underlying disease, rather than antiplatelet therapy per se. The main reasons for respiratory distress after oral (AZD6140), and intravenous (cangrelor) agents may be the development of mild asymptomatic thrombotic thrombocytopenic purpura, fluid retention and dyspnoea because of the reversible nature of these drugs. Also, these agents are ATP analogues, which rapidly metabolise to adenosine, a well-known bronchoprovocator causing dyspnoea as well. In summary, dyspnoea is seldom considered, there are no treatment algorithms when it does occur, plausible mechanisms exist and despite these plausible mechanisms, the true cause of dyspnoea in these exposed individuals is unknown. Additional pulmonary function testing, immunological investigations and platelet receptor studies are urgently needed to determine the cause of dyspnoea after AZD6140, and to point out how such serious adverse reactions can be prevented, or at least minimised, raising potential concerns about this drug. [source] A New Superconducting Phase of Sodium Cobalt Oxide,ADVANCED MATERIALS, Issue 21 2004K. Takada A new superconducting sodium cobalt oxide (see Figure, left) has been synthesized through soft-chemical modification using ,-NaCoO2 as a parent compound, in place of the ,-Na0.7CoO2 used to make the first cobalt oxide superconductor (see Figure, right). A three-layer periodicity of the CoO2 stacking sequence exists in the present material, in contrast to a two-layer one in the previous. The new oxide has a superconducting transition at 4.6,K. [source] A computational study of the carboxylic acid of phloroglucinol in vacuo and in water solutionINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 3 2010Liliana Mammino Abstract 2,4,6-Trihydroxybenzoic acid (FA) is the carboxylic acid of phloroglucinol and, in turn, the parent compound of many biologically active compounds. The biological activities of FA are "extreme" among trihydroxybenzoic acids (e.g., lowest antioxidant activity, highest toxicity toward crustaceans). A complete MP2/6-31++G(d,p) conformational study in vacuo shows that the lowest energy conformers contain two intramolecular hydrogen bonds between the COOH function and the two ortho phenolic OH, with the Z form of COOH preferred over the E form. Comparisons with conformers in which the H-bonds are removed enable fairly reliable evaluations of their energy, because of an off-plane shift of COOH on H-bond removal, decreasing the effects of lone pair repulsion. Comparisons with the other hydroxybenzoic acids (extensively calculated in vacuo at the same level of theory) suggest that FA has the strongest intramolecular H-bonds. PCM calculations of FA in water solution show the same sequence of relative stabilities as in vacuo, with narrower differences because of the greater solvent stabilization of higher energy conformers. Calculations of adducts with water molecules H-bonded to different donor,acceptor centers of FA show the preferred arrangements of water molecules around the different regions of FA and confirm that the stronger intramolecular H-bonds are not broken on competition with the possibility of formation of intermolecular H-bonds. HF/6-31++G(d,p) calculations of adducts, in which the FA molecule is completely surrounded by water molecules, show that 14,16 water molecules (depending on the FA conformer geometry) realize arrangements corresponding to a presumable first solvation layer, with all the water molecules directly H-bonded to donor,acceptor centers of FA or bridging water molecules directly H-bonded to them. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010 [source] Effects of Methyl Substituents on the Activity and Enantioselectivity of Homobenzotetramisole-Based Catalysts in the Kinetic Resolution of AlcoholsADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 14-15 2009Yuhua Zhang Abstract Substitution of the tetrahydropyrimidine ring in the enantioselective acyl transfer catalyst homobenzotetramisole (HBTM) 6 with methyl groups exerts a dramatic influence on its performance in the kinetic resolution of secondary alcohols. The syn- 3-methyl analogue of HBTM (9a) has proved to be superior to the parent compound in terms of catalytic activity, enantioselectivity, and synthetic accessibility. [source] Structure of the quaternary alloy Zn0.6Mn0.4In2S4 from synchrotron powder diffraction and electron transmission microscopyJOURNAL OF APPLIED CRYSTALLOGRAPHY, Issue 1 2006Asiloé J. Mora The aim of the present work was to determine the structure of the quaternary alloy Zn0.6Mn0.4In2S4 and to locate the Mn2+. This was accomplished by means of powder synchrotron X-ray diffraction, high-resolution microscopy and convergent-beam electron diffraction (CBED). The powder X-ray diffraction pattern was indexed in a rhombohedral cell, with cell constants a = 3.875,(2), c = 37.208,(4),Å, and possible space groups Rm or R3m. Rietveld refinements using different cationic arrangements in these space groups were performed. A model in space group R3m, in which the tetrahedral and octahedral sites were occupied by different proportions of Zn, Mn and In atoms, gave the best result. The Rietveld refinement of this model led to figures of merit Rwp = 9.8%, Rp = 9.1% and ,2 = 11.1. Selected-area electron diffraction patterns and high-resolution transmission electron micrographs along [001] reveal the rhombohedral configuration. CBED patterns perpendicular to [001], showing the distinctive 3m symmetry, confirmed space group R3m and the breaking of the centrosymmetry of the parent compound, ZnIn2S4. [source] 2,4,6-Trichlorophenol and phenol removal in methanogenic and partially-aerated methanogenic conditions in a fluidized bed bioreactorJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 10 2005Claudio Garibay-Orijel Abstract A fluidized bed bioreactor (FBBR) was operated for more than 575 days to remove 2,4,6-trichlorophenol (TCP) and phenol (Phe) from a synthetic toxic wastewater containing 80 mg L,1 of TCP and 20 mg L,1 of Phe under two regimes: Methanogenic (M) and Partially-Aerated Methanogenic (PAM). The mesophilic, laboratory-scale FBBR consisted of a glass column (3 L capacity) loaded with 1 L of 1 mm diameter granular activated carbon colonized by an anaerobic consortium. Sucrose (1 g COD L,1) was used as co-substrate in the two conditions. The hydraulic residence time was kept constant at 1 day. Both conditions showed similar TCP and Phe removal (99.9 + %); nevertheless, in the Methanogenic regime, the accumulation of 4-chlorophenol (4CP) up to 16 mg L,1 and phenol up to 4 mg L,1 was observed, whereas in PAM conditions 4CP and other intermediates were not detected. The specific methanogenic activity of biomass decreased from 1.01 ± 0.14 in M conditions to 0.19 ± 0.06 mmolCH4 h,1 gTKN,1 in PAM conditions whereas the specific oxygen uptake rate increased from 0.039 ± 0.008 in M conditions to 0.054 ± 0.012 mmolO2 h,1 gTKN,1, which suggested the co-existence of both methanogenic archaea and aerobic bacteria in the undefined consortium. The advantage of the PAM condition over the M regime is that it provides for the thorough removal of less-substituted chlorophenols produced by the reductive dehalogenation of TCP rather than the removal of the parent compound itself. Copyright © 2005 Society of Chemical Industry [source] Comparison between photocatalytic ozonation and other oxidation processes for the removal of phenols from waterJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 9 2005Fernando J Beltrán Abstract Photocatalytic ozonation (1O3 + VUV + TiO2), ozonation (O3), catalytic ozonation (O3 + TiO2), ozone photolysis (O3 + VUV), photocatalysis (TiO2 + VUV) and photolysis (VUV) have been compared in terms of formation of intermediates, extent of, mineralization (TOC, COD, chloride, nitrate) and kinetics in the aqueous treatment of three phenols (phenol, p -chlorophenol and p -nitrophenol). In all cases, photocatalytic ozonation led to lower degradation times for chemical oxygen demand and total organic carbon removal. Intermediates formed were similar in the different oxidation systems with some exceptions. They can be classified into three different types: polyphenols (resorcinol, catechol, hydroquinone), unsaturated carboxylic acids (maleic and fumaric acids) and saturated carboxylic acids (glyoxylic, formic and oxalic acids). First order kinetic equations have been checked for the oxidation processes studied in the case of the parent compound. Rate constants of these systems have also been calculated. Copyright © 2005 Society of Chemical Industry [source] Efficacy and Safety Evaluation of Ozonation to Degrade Aflatoxin in CornJOURNAL OF FOOD SCIENCE, Issue 8 2002A.D. Prudente Jr. ABSTRACT: This study determined the efficacy and safety of ozonation in degrading aflatoxin in corn. Ozonation (10 to 12 wt%) reduced aflatoxin levels by 92% and no reversion to the parent compound was observed. Ozonation had minimal effect on fatty acids of uncontaminated corn, but had significant effect on fatty acids of contaminated corn. Crude extracts showed no mutagenic potential in the Ames assay using TA98 and TA100. Clean-up using hexane increased their mutagenic potentials. Clean-up using Mycosep columns increased the mutagenic potentials 18 to 617%. Hexane extracts from ozone-treated contaminated corn had lower inhibitory effect. This suggested that a fat-soluble mutagen is being formed or natural inhibitors of mutagenicity are being destroyed. [source] Structure elucidation, conformational analysis and thermal effects on membrane bilayers of an antimicrobial myricetin ether derivativeJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2001C. Demetzos The membrane perturbing 3,7,4,,5,-tetramethyl ether of myricetin 1 was isolated from Cistus monspelien-sis L. Its structure was elucidated and its conformational properties were explored using a combination of 2D NMR spectroscopy and computational chemistry. The obtained results showed that compound 1 adopts four enantiomeric pairs of low energy conformers characterized: (a) by an aromatic ring B twisted through rotation about C2-C1, bond from the rigid isoflavone ring; (b) a 4,-O-CH3 bond oriented out of the plane with equal probability upwards or downwards the phenyl ring B, while all the other O-CH3 bonds are oriented in the plane of the aryl ring. Two of these enantiomeric pairs are lowest in energy. These possible bioactive con-formers are possibly stabilized by van Der Waals interactions. The 3,,5-diacetyl derivative 2 of compound 1 was synthesized and its structure elucidation was achieved based on the chemical shift assignment of the parent compound 1. The Differential Scanning Calorimetry (DSC) results revealed that the degree of the thermal effects exerted by the flavonoids at dipalmitoylphosphatidyl choline (DPPC) bilayers followed the order 1 > 2 > myricetin. Their antimicrobial activity against Gram positive bacteria followed the same order. [source] Synthesis and radiolabelling of Re(CO)3 - , -elemene derivatives as potential therapeutic radiopharmaceuticalsJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 5 2009Yunfeng Ren Abstract , -Elemene, (1S, 2S, 4R)-(,)-(1-methy-1-vinyl-2,4-diisopropenyl cyclohexane) is an anticancer agent from the Traditional Chinese Herb Medicinal. Three novel Re(CO)3 - , -elemene derivatives including their radioactive conjugates containing N,N,N tridentate ligands and tricarbonyl rhenium (complex 12, 13, 14) were synthesized. Their structures were characterized by infrared (IR), 1H-NMR and HRMS. Good radioactive yield (above 90%) and radioactive chemical purity with Re-188 (above 95%) were obtained for all of the three derivatives (complex 15, 16, 17). The antiproliferative activity of non-radioactive , -elemene-Re(CO)3 derivatives on Lewis lung cancer cells and HeLa cell lines were evaluated by WST-1 methods. The result shows substantial decrease in IC50 values compared with the parent compound , -elemene. The synthesis and radiosynthesis of , -elemene tricarbonyl rhenium conjugates provide the possibility to find a new kind of potential radiopharmaceuticals on , -elemene. Copyright © 2009 John Wiley & Sons, Ltd. [source] Studies on the metabolism of the ,9-tetrahydrocannabinol precursor ,9-tetrahydrocannabinolic acid A (,9-THCA-A) in rat using LC-MS/MS, LC-QTOF MS and GC-MS techniquesJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 10 2009Julia Jung Abstract In Cannabis sativa, ,9-Tetrahydrocannabinolic acid-A (,9-THCA-A) is the non-psychoactive precursor of ,9-tetrahydrocannabinol (,9-THC). In fresh plant material, about 90% of the total ,9-THC is available as ,9-THCA-A. When heated (smoked or baked), ,9-THCA-A is only partially converted to ,9-THC and therefore, ,9-THCA-A can be detected in serum and urine of cannabis consumers. The aim of the presented study was to identify the metabolites of ,9-THCA-A and to examine particularly whether oral intake of ,9-THCA-A leads to in vivo formation of ,9-THC in a rat model. After oral application of pure ,9-THCA-A to rats (15 mg/kg body mass), urine samples were collected and metabolites were isolated and identified by liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high resolution LC-MS using time of flight-mass spectrometry (TOF-MS) for accurate mass measurement. For detection of ,9-THC and its metabolites, urine extracts were analyzed by gas chromatography-mass spectrometry (GC-MS). The identified metabolites show that ,9-THCA-A undergoes a hydroxylation in position 11 to 11-hydroxy-,9-tetrahydrocannabinolic acid-A (11-OH-,9-THCA-A), which is further oxidized via the intermediate aldehyde 11-oxo-,9-THCA-A to 11-nor-9-carboxy-,9-tetrahydrocannabinolic acid-A (,9-THCA-A-COOH). Glucuronides of the parent compound and both main metabolites were identified in the rat urine as well. Furthermore, ,9-THCA-A undergoes hydroxylation in position 8 to 8-alpha- and 8-beta-hydroxy-,9-tetrahydrocannabinolic acid-A, respectively, (8,-Hydroxy-,9-THCA-A and 8,-Hydroxy-,9-THCA-A, respectively) followed by dehydration. Both monohydroxylated metabolites were further oxidized to their bishydroxylated forms. Several glucuronidation conjugates of these metabolites were identified. In vivo conversion of ,9-THCA-A to ,9-THC was not observed. Copyright © 2009 John Wiley & Sons, Ltd. [source] Synthesis, conformational analysis and biological activities of lanthionine analogs of a cell adhesion modulatorJOURNAL OF PEPTIDE SCIENCE, Issue 2 2001Haitao Li Abstract Cell adhesion is critical for many biological processes, such as hemostasis, wound healing, tumor metastasis and inflammation. Integrins are important mediators of cell adhesion. The integrin ,4,1, also known as VLA-4, is a cell surface receptor involved in inflammation. A cyclic peptide, 1-FCA-Arg-c[Cys-Asp-Thz-Cys]-OH, is a potent antagonist to VLA-4 with an IC50 of 2.4 n,,. In the current study, we synthesized the lanthionine analogs of 1-FCA-Arg-c[Cys-Asp-Thz-Cys]-OH and determined the conformations of both the parent compound and its lanthionine analog in solution by NMR and computer simulations. The lanthionine analog retains its selectivity to VLA-4 with high nanomolar potency. Both molecules adopt similar topological arrangements in their conformations, while some important differences remain in the sulfur bridge region, which may cause the difference in potency. Copyright © 2001 European Peptide Society and John Wiley & Sons, Ltd. [source] New insights into the biotransformation and pharmacokinetics of oxaliplatinJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2009Elin Jerremalm Abstract Oxaliplatin is used primarily in the treatment of metastatic colorectal cancer. In this minireview, we discuss potentially important biotransformation pathways in light of its short elimination half-life in vivo. We also highlight new information achieved using a selective analytical technique to measure intact oxaliplatin in pharmacokinetic studies (comprising intravenous, intraperitoneal, and intrahepatic administration) and compare to results obtained by measurements of total platinum. The use of selective analytical techniques is strongly recommended giving kinetic parameters of the parent compound and not only to a complex mixture of platinum containing endogenous compounds. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3879,3885, 2009 [source] In-vitro transdermal penetration of cytarabine and its N4-alkylamide derivativesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2010Lesetja J. Legoabe Abstract Objectives The aim of this study was to synthesise and determine the transdermal penetration of cytarabine alkylamide derivatives and assess the correlation of flux with physicochemical properties. Methods The alkylamide derivatives of cytarabine were synthesised by acylation at the N4-amino group by the mixed anhydride method. The in-vitro permeation studies were performed using the Franz diffusion cell methodology. Furthermore, partition coefficients (n -octanol,water) and aqueous solubility of the N4-alkylamide derivatives of cytarabine were determined in order to obtain information about their lipophilicity and hydrophilicity. Key findings The N4-alkylamides of cytarabine (acetyl, butanoyl, hexanoyl, octanoyl, and decanoyl derivatives) showed decreased hydrophilicity and increased lipophilicity. The log D values of the alkylamides were higher than that of the parent compound and increased linearly as the alkyl chain lengthened. N4-hexanoyl-4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl] pyrimidin-2-one) showed the highest median steady-state flux (Jss) of 89.0 nmol/cm2 per h in the series, which shows a high statistical difference with the parent compound flux value (3.70 nmol/cm2 per h). Conclusions The prodrug approach appears to be a promising strategy for the enhancement of transdermal penetration of cytarabine. [source] Cyamemazine metabolites: effects on human cardiac ion channels in-vitro and on the QTc interval in guinea pigsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2008William Crumb Monodesmethyl cyamemazine and cyamemazine sulfoxide, the two main metabolites of the antipsychotic and anxiolytic phenothiazine cyamemazine, were investigated for their effects on the human ether-à-go-go related gene (hERG) channel expressed in HEK 293 cells and on native INa, ICa, Ito, Isus or IK1 of human atrial myocytes. Additionally, cyamemazine metabolites were compared with terfenadine for their effects on the QT interval in anaesthetized guinea pigs. Monodesmethyl cyamemazine and cyamemazine sulfoxide reduced hERG current amplitude, with IC50 values of 0.70 and 1.53 ,M, respectively. By contrast, at a concentration of 1 ,M, cyamemazine metabolites failed to significantly affect INa, Ito, Isus or IK1 current amplitudes. Cyamemazine sulfoxide had no effect on ICa at 1 ,M, while at this concentration, monodesmethyl cyamemazine only slightly (17%), albeit significantly, inhibited ICa current. Finally, cyamemazine metabolites (5 mg kg,1 i.v.) were unable to significantly prolong QTc values in the guinea pig. Conversely, terfenadine (5 mg kg,1 i.v.) significantly increased QTc values. In conclusion, cyamemazine metabolite concentrations required to inhibit hERG current substantially exceed those necessary to achieve therapeutic activity of the parent compound in humans. Moreover, cyamemazine metabolites, in contrast to terfenadine, do not delay cardiac repolarization in the anaesthetized guinea pig. These non-clinical findings explain the excellent cardiac safety records of cyamemazine during its 30 years of extensive therapeutic use. [source] Clinical (Nonforensic) Application of Ethyl Glucuronide Measurement: Are We Ready?ALCOHOLISM, Issue 6 2010Peter Jatlow Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are minor metabolites of ethanol. Multiple studies have documented that, depending upon the amount of alcohol consumed, they can be measured in biological fluids for hours to days after the parent compound can no longer be detected. Testing for the presence of EtG, in a manner analogous to urinary drug abuse screening, has largely been restricted to forensic and law enforcement situations. Despite a real need for an objective and possibly quantitative marker of ethanol exposure for use in conjunction with outpatient clinical trials and treatment programs, measurement of these metabolites has seen only limited clinical application. The barriers to more extensive clinical use of EtG/EtS testing, particularly misleading assay results that can occur as a consequence of inadvertent exposure to nonbeverage ethanol-containing substances, are reviewed and put into perspective. Additional information needed to develop guidelines for optimal clinical utilization of EtG/EtS measurements is discussed. [source] | ||||||||||||||||||||||||||||||||||||||||