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Sample records for cholinesterase inhibitors annual

  1. Effect of cholinesterase inhibitors on attention.

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    Pepeu, Giancarlo; Giovannini, Maria Grazia; Bracco, Laura

    2013-03-25

    Advantages and limits of the use of cholinesterase inhibitors (ChEI) in Alzheimer's disease (AD) are well established. Their effects result from an increase in extracellular acetylcholine (ACh) whose hydrolysis is prevented by cholinesterase inhibition. In this way, the cholinergic deficit which characterizes AD may be corrected. This overview discusses which components of the cognitive process are improved by ChEI administration. In animal experiments, the increase in ACh release, detected in brain areas during behavioral tasks designed to tax attentional processes, demonstrates that an activation of cholinergic neurons underlies arousal and attention. Since arousal and attention depend on activation of the forebrain cholinergic system, it is to be expected that the loss of cholinergic neurons occurring in AD may lead to impairment of the attentional processes. Indeed, a consensus exists that attention is the first non-memory domain to be affected in AD, before deficits in language and visuo-spatial functions. The difficulties with daily living, which occur even in mild AD, may be related to attentional deficits. ChEIs, by restoring the cholinergic activity, should improve attention. If the cognitive changes resulting from ChEI treatment in AD patients are assessed with appropriate tests or selected items of the scales, a predominant effect on attention and executive functions emerges. In a group of 121 subjects with mild to moderate AD, (MMSE score 21.88 ± 3.63) followed in the Alzheimer Unit in Florence, after a year of treatment with standard doses of ChEIs, it was observed a stabilization of the disease, characterized by no changes of the tests evaluating attention and executive functions but a worsening of those involving memory mechanisms. These findings suggest that ChEI treatment preserves attention more than memory. Finally, the electrophysiological and neurochemical mechanisms through which the activation of the cholinergic forebrain neurons enhance

  2. Structure-Based Search for New Inhibitors of Cholinesterases

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    Barbara Malawska

    2013-03-01

    Full Text Available Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with IC50 values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors.

  3. Proline-Based Carbamates as Cholinesterase Inhibitors

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    Hana Pizova

    2017-11-01

    Full Text Available Series of twenty-five benzyl (2S-2-(arylcarbamoylpyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE and butyrylcholinesterase (BChE, and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S-2-[(2-chlorophenylcarbamoyl]pyrrolidine-1-carboxylate (IC50 = 46.35 μM was the most potent agent. On the other hand, benzyl (2S-2-[(4-bromophenyl-] and benzyl (2S-2-[(2-bromophenylcarbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 μM, respectively comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S-2-[(2-hydroxyphenylcarbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure–inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA and principal component analysis (PCA. Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3′-/4′-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE.

  4. Blood cholinesterase in rats fed an insect resistance apple clone containing a natural cholinesterase inhibitor.

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    Stoewsand, G S; Anderson, J L; Brown, S K

    1994-01-01

    A crab apple clone (Malus brevipes 1021), highly resistant to the apple maggot, is being used in breeding programs developing commercial apple cultivars. This study has discovered that this crab apple contains a natural cholinesterase (ChE) inhibitor that caused a 17.5% in vitro inhibition of rat blood ChE activity. This crab apple also showed a relatively high total (titratable) acidity of 1.28%. The commercial, nonresistant, apple cultivar McIntosh was capable of causing a 7.9% inhibition of blood ChE in vitro. The total acidity in McIntosh was 0.45%. A 4-wk feeding study compared 2 groups of 5-wk-old Fischer 344 male rats fed diets containing 45% of either M. brevipes or McIntosh freeze-dried apples to a third (control) group of rats fed a semipurified diet. In vivo blood ChE activities were similar in all groups of rats, as well as hemoglobin, hematocrit, and red blood cell counts. The liver mixed-function oxidase activity through aminopyrine N-demethylase in the rats fed the apple diets was higher than the controls, but p-nitroanisole O-demethylase activity was induced only in the animals fed the maggot-resistant crab apple. Lowered growth with concomitant lowered food intake, in the otherwise healthy rats fed the maggot-resistant crab apple diet, was attributed to the less palatable, highly acidic fruit. This study indicates that the natural ChE inhibitor in the insect-resistant apple M. brevipes is apparently detoxified upon ingestion.

  5. Persistence of Cholinesterase Inhibitor Treatment in Dementia: Insights from a Naturalistic Study

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    Javier Olazarán

    2013-03-01

    Full Text Available Background: Cholinesterase inhibitors (ChEI are widely used in dementia, but there is a lack of practice guidelines in case of intolerance or absence of perceived effect. Methods: Two hundred and forty patients (mean age 77 years, SD 6.3, 66% female with Alzheimer's disease or Lewy body dementia were prescribed a ChEI and evaluated annually under conditions of standard practice. Of these, 152 patients maintained, 36 switched, and 52 abandoned ChEI treatment. Results: Less behavioural disturbance and less cognitive deterioration were observed, respectively, at the 3- and 4-year follow-up assessments in the patients who maintained the first prescribed ChEI (p Conclusions: Maintenance of the first prescribed ChEI was supported when some benefit was perceived by the patient or caregiver, even in cases of nonserious adverse events.

  6. Effects of acute and repeated administration of cholinesterase inhibitor on timing behaviour

    NARCIS (Netherlands)

    Bouger, P.C.; Spowart-Manning, L.; Ferrara, A.; Schmidt, B.H.; Staay, van der F.J.

    2004-01-01

    It has been hypothesised that a leftward shift in the response distribution obtained in the peak interval (PI) procedure is a characteristic of cognitive enhancement in which mental processes are speeded. Metrifonate, a cholinesterase inhibitor with reported cognitive enhancing properties in many

  7. Effects of Cholinesterase Inhibitors in Parkinson's Disease Dementia : A Review of Clinical Data

    NARCIS (Netherlands)

    van Laar, Teus; De Deyn, Peter Paul; Aarsland, Dag; Barone, Paolo; Galvin, James E.

    2011-01-01

    Aims: Cognitive impairment and dementia are common features of Parkinson's disease (PD). Patients with Parkinson's disease dementia (PDD) often have significant cholinergic defects, which may be treated with cholinesterase inhibitors (ChEIs). The objective of this review was to consider available

  8. Pharmacology and toxicology of cholinesterase inhibitors: uses and misuses of a common mechanism of action.

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    Pope, Carey; Karanth, Subramanya; Liu, Jing

    2005-05-01

    Cholinesterase inhibitors have been used in the treatment of human diseases, the control of insect pests, and more notoriously as chemical warfare agents and weapons of terrorism. Most uses of cholinesterase inhibitors are based on a common mechanism of action initiated by inhibition of acetylcholinesterase (AChE). Extensive inhibition of this enzyme leads to accumulation of the neurotransmitter acetylcholine and enhanced stimulation of postsynaptic cholinergic receptors. This action is beneficial in cases where a reduction in cholinergic transmission contributes to clinical symptoms, e.g., low muscle tone in the autoimmune disorder myasthenia gravis due to loss of nicotinic receptors. Under normal conditions, however, extensive inhibition of AChE leads to excess synaptic acetylcholine levels, over-stimulation of cholinergic receptors, alteration of postsynaptic cell function and consequent signs of cholinergic toxicity. This biochemical cascade forms the basis for the use of anticholinesterase insecticides in pest control as well as for nerve agents in chemical warfare. Paradoxically, the short-acting cholinesterase inhibitor pyridostigmine, an important therapeutic agent in the treatment of myasthenia gravis, was used during the Persian Gulf War to prevent the long-term clinical consequences of possible organophosphate nerve agent exposure. As shown in the attacks in Matsumoto and Tokyo, these same nerve agents can be effectively used to inflict urban terror. Cholinesterase inhibitors thus share a common mechanism of pharmacological or toxicological action, ultimately modifying cholinergic signaling through disruption of acetylcholine degradation. While the use of cholinesterase inhibitors relies on their interaction with AChE, a variety of reports indicate that a number of cholinesterase inhibitors have additional sites of action that may have pharmacologic or toxicologic relevance. A variety of esterase and non-esterase enzymes, neurotransmitter receptors and

  9. Molecular design and synthesis of novel peptides from amphibians skin acting as inhibitors of cholinesterase enzymes.

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    Siano, Alvaro; Garibotto, Francisco F; Andujar, Sebastian A; Baldoni, Hector A; Tonarelli, Georgina G; Enriz, Ricardo D

    2017-03-01

    Cholinesterases are a family of enzymes that catalyze the hydrolysis of neurotransmitter acetylcholine. There are two types of cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which differ in their distribution in the body. Currently, cholinesterase inhibitors (ChEI) represent the treatment of choice for Alzheimer's disease (AD). In this paper, we report the synthesis and inhibitory effect on both enzymes of four new peptides structurally related to P1-Hp-1971 (amphibian skin peptide found in our previous work. Sequence: TKPTLLGLPLGAGPAAGPGKR-NH2 ). The bioassay data and cytotoxicity test show that some of the compounds possess a significant AChE and BChE inhibition and no toxic effect. The present work demonstrates that diminution of the size of the original peptide could potentially result in new compounds with significant cholinesterase inhibition activity, although it appears that there is an optimal size for the sequence. We also conducted an exhaustive molecular modeling study to better understand the mechanism of action of these compounds by combining docking techniques with molecular dynamics simulations on BChE. This is the first report about amphibian peptides and the second one of natural peptides with ChE inhibitory activity. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

  10. Development of Cholinesterase Inhibitors Using (a)-Lipoic Acid-benzyl Piperazine Hybrid Molecules

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    Kim, Beomcheol; Lee, Seunghwan; Jang, Mi; Shon, Min Young; Park, Jeong Ho [Hanbat National Univ., Daejeon (Korea, Republic of)

    2013-11-15

    A series of hybrid molecules between (α)-lipoic acid (ALA) and benzyl piperazines were synthesized and their in vitro cholinesterase [acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)] inhibitory activities were evaluated. Even though the parent compounds did not show any inhibitory activity against cholinesterase (ChE), all hybrid molecules showed BuChE inhibitory activity. Some hybrid compounds also displayed AChE inhibitory activity. Specifically, ALA-1-(3-methylbenzyl)piperazine (15) was shown to be an effective inhibitor of both BuChE (IC{sub 50} = 2.3 ± 0.7 μM) and AChE (IC{sub 50} = 30.31 ± 0.64 μM). An inhibition kinetic study using compound 15 indicated a mixed inhibition type. Its binding affinity (K{sub i}) value to BuChE is 2.91 ± 0.15 μM.

  11. [How aliphatic alcohols and ph affect reactional capability of the horse blood serum cholinesterase at its interaction with organophosphorus inhibitors].

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    Basova, N E; Kormilitsin, B N; Perchenok, A Iu; Rozengart, E V; Saakov, V S; Suvorov, A A

    2013-01-01

    There was studied action of aliphatic alcohols (ethanol, propanol, isopropanol, n-butanol, isobutanol, secbutanol, tretbetanol) and pH on various kinds of reactional capability the serum cholinesterase. At the alcohols-affected inhibition of the cholinesterase hydrolytic activity, the determining role was played not the total number carbon atoms in the alcohol molecule, but by the "effective length" of the carbohydrate chain. The fact that the presence of alcohols did not affect parameters of the reverse cholinesterase inhibition with onium ions tetramethylammonium and choline allows suggesting the absence of effect solvents on specific acetylcholine sorption in the enzyme active center. With aid of two rows of hydrophobic organophosphorus inhibitors (OPI), we have managed to estimate both the degree and the character itself of the modifying action of alcohols and pH on the process of irreversible inhibition of serum cholinesterase.

  12. Cholinesterase inhibitor (Altenuene) from an endophytic fungus Alternaria alternata: optimization, purification and characterization.

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    Bhagat, J; Kaur, A; Kaur, R; Yadav, A K; Sharma, V; Chadha, B S

    2016-10-01

    The aim of this study was to screen endophytic fungi isolated from Vinca rosea for their potential to produce acetylcholinesterase (AChE) inhibitors. Endophytic fungi isolated from V. rosea (Catharanthus roseus), were screened for AChE inhibitor production using Ellman's method. Maximum inhibition against AChE (78%) was observed in an isolate VS-10, identified to be Alternaria alternata on morphological and molecular basis. The isolate also inhibited butyrylcholinesterase (73%). Significant increase (1·3 fold) was achieved after optimization of process parameters using one variable at time approach. The inhibitor was purified using chromatographic techniques. The structure elucidation of the inhibitor was carried out using spectroscopic techniques and was identified to be 'altenuene'. The purified inhibitor possessed antioxidant potential as revealed by dot blot assay. The insecticidal potential of purified inhibitor was evaluated by feeding Spodoptora litura on diet amended with inhibitor. It evinced significant larval mortality. Endophytic A. alternata can serve as a source of dual cholinesterase inhibitor 'altenuene' with significant antioxidant and insecticidal activity. This is the first report on acetylcholinestearse inhibitory activity of altenuene. Alternaria alternata has the potential to produce a dual ChE inhibitor with antioxidant activity useful in the treatment of neurodegenerative disorders and in agriculture as biocontrol agent. © 2016 The Society for Applied Microbiology.

  13. Predictors of Response to Cholinesterase Inhibitors Treatment of Alzheimer's Disease: Date Mining from the TREDEM Registry.

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    Gallucci, Maurizio; Spagnolo, Pierpaolo; Aricò, Maria; Grossi, Enzo

    2016-01-01

    The pharmacological treatment of Alzheimer's disease (AD) is based largely on cholinesterase inhibitors (ChEI). To investigate whether or not some non-pharmacological and contextual factors measured prior to starting treatment such as past occupation, lifestyles, marital status, degree of autonomy and cognitive impairment, living alone or with others, and the degree of brain atrophy are associated with a better response to ChEI treatment. Eighty-four AD and six AD with cerebrovascular disease (AD + CVD) outpatients of Treviso Dementia (TREDEM) Registry, with an average cholinesterase inhibitors treatment length of four years, were considered. The outpatients had undergone a complete evaluation and some non-pharmacological and contextual factors were collected. We defined responder a patient with a delta score T0 - T1 equal or inferior to 2.0 points per year of MMSE and a non-responder a patient with a delta score T0 - T1 superior to 2.0 points per year. In order to identify hidden relationships between variables related to response and non-response, we use a special kind of artificial neural network called Auto-CM, able to create a semantic connectivity map of the variables considered in the study. A higher cognitive profile, a previous intellectual occupation, healthier lifestyles, being married and not living alone, a higher degree of autonomy, and lower degree of brain atrophy at baseline resulted in affecting the response to long-term ChEI therapy. Non-pharmacological and contextual factors appear to influence the effectiveness of treatment with ChEI in the long term.

  14. Cholinesterase inhibitors improve both memory and complex learning in aged beagle dogs.

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    Araujo, Joseph A; Greig, Nigel H; Ingram, Donald K; Sandin, Johan; de Rivera, Christina; Milgram, Norton W

    2011-01-01

    Similar to patients with Alzheimer's disease (AD), dogs exhibit age-dependent cognitive decline, amyloid-β (Aβ) pathology, and evidence of cholinergic hypofunction. The present study sought to further investigate the role of cholinergic hypofunction in the canine model by examining the effect of the cholinesterase inhibitors phenserine and donepezil on performance of two tasks, a delayed non-matching-to-position task (DNMP) designed to assess working memory, and an oddity discrimination learning task designed to assess complex learning, in aged dogs. Phenserine (0.5 mg/kg; PO) significantly improved performance on the DNMP at the longest delay compared to wash-out and partially attenuated scopolamine-induced deficits (15 μg/kg; SC). Phenserine also improved learning on a difficult version of an oddity discrimination task compared to placebo, but had no effect on an easier version. We also examined the effects of three doses of donepezil (0.75, 1.5, and 6 mg/kg; PO) on performance of the DNMP. Similar to the results with phenserine, 1.5 mg/kg of donepezil improved performance at the longest delay compared to baseline and wash-out, indicative of memory enhancement. These results further extend the findings of cholinergic hypofunction in aged dogs and provide pharmacological validation of the canine model with a cholinesterase inhibitor approved for use in AD. Collectively, these studies support utilizing the aged dog in future screening of therapeutics for AD, as well as for investigating the links among cholinergic function, Aβ pathology, and cognitive decline.

  15. Potentiation by cholinesterase inhibitors of cholinergic activity in rat isolated stomach and colon.

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    Jarvie, Emma M; Cellek, Selim; Sanger, Gareth J

    2008-01-01

    Acetylcholinesterase (AChE) inhibitors stimulate gastrointestinal (GI) motility and are potential treatments of conditions associated with inadequate GI motility. The ability of itopride to facilitate neuronally (predominantly cholinergic) mediated contractions of rat isolated stomach, evoked by electrical field stimulation (EFS), has been compared with other cholinesterase inhibitors and with tegaserod, a clinically effective prokinetic and non-selective 5-HT(4) receptor agonist which also facilitates GI cholinergic function. Neostigmine greatly increased EFS-evoked contractions over a narrow concentration range (0.01-1 microM; 754+/-337% facilitation at 1 microM); higher concentrations (1, 3 microM) also increased muscle tension. Donepezil increased EFS-evoked contractions gradually over the full range of concentrations (0.01-10 microM; maximum increase 516+/-20% at 10 microM). Itopride increased the contractions even more gradually, rising to 188+/-84% at 10 microM. The butyrylcholinesterase inhibitor iso-OMPA 0.01-10 microM also increased EFS-evoked contractions, to a maximum of 36+/-5.0% at 10 microM, similar to that caused by tegaserod (35+/-5.2% increase at 1 microM). The effects of tegaserod, but not itopride were inhibited by the 5-HT(4) receptor antagonist SB-204070A 0.3 microM. In rat isolated colon, neostigmine was again the most efficacious, causing a defined maximum increase in EFS-evoked contractions (343+/-82% at 10 microM), without changing muscle tension. Maximum increases caused by donepezil and itopride were, respectively, 57.6+/-20 and 43+/-15% at 10 microM. These data indicate that the abilities of different AChE inhibitors to increase GI cholinergic activity differ markedly. Understanding the reasons is essential if AChE inhibitors are to be optimally developed as GI prokinetics.

  16. Pharmacological treatment of Alzheimer disease: from psychotropic drugs and cholinesterase inhibitors to pharmacogenomics.

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    Cacabelos, R; Alvarez, A; Lombardi, V; Fernández-Novoa, L; Corzo, L; Pérez, P; Laredo, M; Pichel, V; Hernández, A; Varela, M; Figueroa, J; Prous, J; Windisch, M; Vigo, C

    2000-07-01

    For the past 20 years the scientific community and the pharmaceutical industry have been searching for treatments to neutralize the devastating effects of Alzheimer disease (AD). During this period important changes in the etiopathogenic concept of AD have occurred and, as a consequence, the pharmacological approach for treating AD has also changed. During the past 2 decades only 3 drugs for AD have been formally approved by the FDA, although in many countries there are several drugs which are currently used as neuroprotecting agents in dementia alone or in combination with cholinesterase inhibitors. The interest of the pharmaceutical industry has also shifted from the cholinergic hypothesis which led to the development of cholinesterase inhibitors to enhance the bioavailability of acetylcholine at the synaptic cleft to a more "molecular approach" based on new data on the pathogenic events underlying neurodegeneration in AD. In our opinion, the pharmacological treatment of AD should rely on a better understanding of AD etiopathogenesis in order to use current drugs that protect the AD brain against deleterious events and/or to develop new drugs specifically designed to inhibit and/or regulate those factors responsible for premature neuronal death in AD. The most relevant pathogenic events in AD can be classified into main categories: primary events (genetic factors, neuronal apoptosis), secondary events (beta-amyloid deposition in senile plaques and brain vessels, neurofibrillary tangles due to hyperphosphorylation of tau proteins, synaptic loss), tertiary events (neurotransmitter deficits, neurotrophic alterations, neuroimmune dysfunction, neuroinflammatory reactions) and quaternary events (excitotoxic reactions, calcium homeostasis miscarriage, free radical formation, primary and/or reactive cerebrovascular dysfunction). All of these pathogenic events are potential targets for treatment in AD. Potential therapeutic strategies for AD treatment include palliative

  17. Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada.

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    Thibault B Ali

    Full Text Available This survey analyzes two national pharmacovigilance databases in order to determine the major adverse reactions observed with the use of cholinesterase inhibitors in dementia. We conducted a statistical analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS and the Canada Vigilance Adverse Reaction Database (CVARD concerning the side effects of cholinesterase inhibitors. The statistics calculated for each adverse event were the frequency and the reporting odds ratios (ROR. A total of 9877 and 2247 reports were extracted from the FAERS and CVARD databases, respectively. A disproportionately higher frequency of reports of death as an adverse event for rivastigmine, compared to the other acetylcholinesterase inhibiting drugs, was observed in both the FAERS (ROR = 3.42; CI95% = 2.94-3.98; P<0.0001 and CVARD (ROR = 3.67; CI95% = 1.92-7.00; P = 0.001 databases. While cholinesterase inhibitors remain to be an important therapeutic tool against Alzheimer's disease, the disproportionate prevalence of fatal outcomes with rivastigmine compared with alternatives should be taken into consideration.

  18. Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

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    Martin Krátký

    2016-02-01

    Full Text Available Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thiocarbamates were investigated using Ellman’s method for their ability to inhibit acetylcholinesterase (AChE and butyrylcholinesterase (BChE. O-Aromatic (thiocarbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thiocarbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenylcarbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM, while 2-(phenylcarbamoylphenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM. Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

  19. Cognitive and affective changes in mild to moderate Alzheimer's disease patients undergoing switch of cholinesterase inhibitors: a 6-month observational study.

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    Gianfranco Spalletta

    Full Text Available Patients with Alzheimer's disease after an initial response to cholinesterase inhibitors may complain a later lack of efficacy. This, in association with incident neuropsychiatric symptoms, may worsen patient quality of life. Thus, the switch to another cholinesterase inhibitor could represent a valid therapeutic strategy. The aim of this study was to investigate the effectiveness of the switch from one to another cholinesterase inhibitor on cognitive and affective symptoms in mild to moderate Alzheimer disease patients. Four hundred twenty-three subjects were included from the EVOLUTION study, an observational, longitudinal, multicentre study conducted on Alzheimer disease patients who switched to different cholinesterase inhibitor due either to lack/loss of efficacy or response, reduced tolerability or poor compliance. All patients underwent cognitive and neuropsychiatric assessments, carried out before the switch (baseline, and at 3 and 6-month follow-up. A significant effect of the different switch types was found on Mini-Mental State Examination score during time, with best effectiveness on mild Alzheimer's disease patients switching from oral cholinesterase inhibitors to rivastigmine patch. Depressive symptoms, when measured using continuous Neuropsychiatric Inventory values, decreased significantly, while apathy symptoms remained stable over the 6 months after the switch. However, frequency of both depression and apathy, when measured categorically using Neuropsychiatric Inventory cut-off scores, did not change significantly during time. In mild to moderate Alzheimer disease patients with loss of efficacy and tolerability during cholinesterase inhibitor treatment, the switch to another cholinesterase inhibitor may represent an important option for slowing cognitive deterioration. The evidence of apathy stabilization and the positive tendency of depressive symptom improvement should definitively be confirmed in double-blind controlled

  20. Functional response to cholinesterase inhibitor therapy in a naturalistic Alzheimer’s disease cohort

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    Wattmo Carina

    2012-11-01

    Full Text Available Abstract Background Activities of daily living (ADL are an essential part of the diagnostic criteria for Alzheimer’s disease (AD. A decline in ADL affects independent living and has a strong negative impact on caregiver burden. Functional response to cholinesterase inhibitor (ChEI treatment and factors that might influence this response in naturalistic AD patients need investigating. The aim of this study was to identify the socio-demographic and clinical factors that affect the functional response after 6 months of ChEI therapy. Methods This prospective, non-randomised, multicentre study in a routine clinical setting included 784 AD patients treated with donepezil, rivastigmine or galantamine. At baseline and after 6 months of treatment, patients were assessed using several rating scales, including the Instrumental Activities of Daily Living (IADL scale, Physical Self-Maintenance Scale (PSMS and Mini-Mental State Examination (MMSE. Demographic and clinical characteristics were investigated at baseline. The functional response and the relationships of potential predictors were analysed using general linear models. Results After 6 months of ChEI treatment, 49% and 74% of patients showed improvement/no change in IADL and in PSMS score, respectively. The improved/unchanged patients exhibited better cognitive status at baseline; regarding improved/unchanged PSMS, patients were younger and used fewer anti-depressants. A more positive functional response to ChEI was observed in younger individuals or among those having the interaction effect of better preserved cognition and lower ADL ability. Patients with fewer concomitant medications or those using NSAIDs/acetylsalicylic acid showed a better PSMS response. Conclusions Critical characteristics that may influence the functional response to ChEI in AD were identified. Some predictors differed from those previously shown to affect cognitive response, e.g., lower cognitive ability and older age

  1. Pharmacogenomics in Alzheimer's disease: a genome-wide association study of response to cholinesterase inhibitors.

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    Martinelli-Boneschi, Filippo; Giacalone, Giacomo; Magnani, Giuseppe; Biella, Gloria; Coppi, Elisabetta; Santangelo, Roberto; Brambilla, Paola; Esposito, Federica; Lupoli, Sara; Clerici, Francesca; Benussi, Luisa; Ghidoni, Roberta; Galimberti, Daniela; Squitti, Rosanna; Confaloni, Annamaria; Bruno, Giuseppe; Pichler, Sabrina; Mayhaus, Manuel; Riemenschneider, Matthias; Mariani, Claudio; Comi, Giancarlo; Scarpini, Elio; Binetti, Giuliano; Forloni, Gianluigi; Franceschi, Massimo; Albani, Diego

    2013-06-01

    We conducted a genome-wide association study in a cohort of 176 Italian Alzheimer's disease (AD) patients with extreme phenotype of response to cholinesterase inhibitors. Patients were classified into responders in case of positive, stable, or ≤1 worsening of mini-mental state examination score and into nonresponders if >3 points worsening during a median follow-up of 0.85 years of treatment. Forty-eight single-nucleotide polymorphisms were selected for replication in 198 additional AD-treated patients. By using the dichotomous response trait and a quantitative trait approach (change of mini-mental state examination), a nominal replication and evidence of association when combining data were achieved for 2 single-nucleotide polymorphisms associated with response to treatment: rs6720975A (pcombined = 2.9 × 10(-5), beta regression coefficient: 1.61) and rs17798800A (pcombined = 6.8 × 10(-6), odds ratio = 0.38, 95% confidence interval = 0.25-0.58). Rs6720975 maps in the intronic region of PRKCE, a protein kinase involved in several cellular functions, whereas rs17798800 is intergenic and, according to expression quantitative trait locus (eQTL) analysis, it acts as a cis-regulator of NBEA, an A kinase-anchoring protein playing a substantial role in the maturation of the nervous system. Despite its limitations, this project paves the way for the application of personalized medicine in AD patients and for collaborative efforts in this field. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Transthyretin as a potential CSF biomarker for Alzheimer's disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors

    DEFF Research Database (Denmark)

    Schultz, K; Nilsson, K; Nielsen, Jørgen Erik

    2010-01-01

    BACKGROUND: Previous studies have indicated that transthyretin (TTR) levels in cerebrospinal fluid (CSF) are altered in depression and dementia. The present study aimed to investigate whether CSF TTR can be used to discriminate between patients with Alzheimer's disease (AD) and patients...... compared to those AD patients who were not. CONCLUSIONS: Significant reductions in CSF TTR were found after cholinesterase inhibitor treatment in patients with AD compared to untreated individuals. CSF TTR was unaltered in patients with DLB and had no relationship to depression in the present cohort...

  3. Impact of geriatric comorbidity and polypharmacy on cholinesterase inhibitors prescribing in dementia

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    Hoffmann Falk

    2011-12-01

    Full Text Available Abstract Background Although most guidelines recommend the use of cholinesterase inhibitors (ChEIs for mild to moderate Alzheimer's Disease, only a small proportion of affected patients receive these drugs. We aimed to study if geriatric comorbidity and polypharmacy influence the prescription of ChEIs in patients with dementia in Germany. Methods We used claims data of 1,848 incident patients with dementia aged 65 years and older. Inclusion criteria were first outpatient diagnoses for dementia in at least three of four consecutive quarters (incidence year. Our dependent variable was the prescription of at least one ChEI in the incidence year. Main independent variables were polypharmacy (defined as the number of prescribed medications categorized into quartiles and measures of geriatric comorbidity (levels of care dependency and 14 symptom complexes characterizing geriatric patients. Data were analyzed by multivariate logistic regression. Results On average, patients were 78.7 years old (47.6% female and received 9.7 different medications (interquartile range: 6-13. 44.4% were assigned to one of three care levels and virtually all patients (92.0% had at least one symptom complex characterizing geriatric patients. 13.0% received at least one ChEI within the incidence year. Patients not assigned to the highest care level were more likely to receive a prescription (e.g., no level of care dependency vs. level 3: adjusted Odds Ratio [OR]: 5.35; 95% CI: 1.61-17.81. The chance decreased with increasing numbers of symptoms characterizing geriatric patients (e.g., 0 vs. 5+ geriatric complexes: OR: 4.23; 95% CI: 2.06-8.69. The overall number of prescribed medications had no influence on ChEI prescription and a significant effect of age could only be found in the univariate analysis. Living in a rural compared to an urban environment and contacts to neurologists or psychiatrists were associated with a significant increase in the likelihood of receiving Ch

  4. Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials.

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    Roberto Raschetti

    2007-11-01

    Full Text Available Mild cognitive impairment (MCI refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD, in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine in delaying the conversion from MCI to Alzheimer disease or dementia.The terms "donepezil", "rivastigmine", "galantamine", and "mild cognitive impairment" and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine. Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y to 25% (over 3 y among treated patients, and from 18% (over 2 y to 28% (over 3 y among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of

  5. Characterization of O,O-diethylphosphoryl oximes as inhibitors of cholinesterases and substrates of phosphotriesterases.

    Science.gov (United States)

    Leader, H; Vincze, A; Manisterski, B; Rothschild, N; Dosoretz, C; Ashani, Y

    1999-08-01

    Reactivators of organophosphate (OP)-inhibited cholinesterases (ChEs) are believed to give rise to phosphorylated oximes (POX) that reinhibit the enzyme. Diethylphosphoryl oximes (DEP-OX) that were generated in situ were demonstrated in the past to be unstable, yet were more potent inhibitors of acetylcholinesterase (AChE) than the parent OPs. In view of the inconsistencies among reported results, and the potential toxicity of POXs, it seemed important to characterize authentic DEP-OXs, and to evaluate their interference with reactivation of diethylphosphoryl-ChE (DEP-ChE) conjugates. To this end, the diethylphosphoric acid esters of 1-methyl-2-pyridinium carboxaldehyde oxime (DEP-2PAM) and 1-methyl-4 pyridinium carboxaldehyde oxime (DEP-4PAM) were synthesized and chemically defined. The half-lives of DEP-2PAM and DEP-4PAM in 10 mM Tris buffer, pH 7.8, at 29 degrees were found to be 10 and 980 sec, respectively. The two DEP-OXs inhibited ChEs with the following ranking order: for DEP-2PAM, human butyrylcholinesterase (HuBChE, k(i) = 2.03 x 10(9) M(-1) min(-1)) > mouse AChE (MoAChE) approximately equal to fetal bovine serum AChE (FBS-AChE) approximately equal to equine BChE (EqBChE); for DEP-4PAM, HuBChE (k(i) = 0.71 x 10(9) M(-1) min(-1)) > EqBChE > MoAChE > FBS-AChE. A dialkylarylphosphate hydrolase (phosphotriesterase; PTE) from Pseudomonas sp. catalyzed the hydrolysis of DEP-4PAM with k(cat)/Km = 3.56 x 10(7) M(-1) min(-1) and Km = 0.78 mM. Reactivation of DEP-ChEs was enhanced by PTE when 4-PAM-based oximes were used as reactivators, whereas reactivation with 2-PAM-based oximes was not affected by PTE. This observation is attributed primarily to the short half-life of DEP-OXs derived from the latter oximes. Relatively low doses of PTE can detoxify large quantities of DEP-OXs rapidly, and thereby augment the efficacy of antidotes that contain the oxime function in position 4 of the pyridine ring.

  6. Adverse Drug Reactions Reported With Cholinesterase Inhibitors : An Analysis of 16 Years of Individual Case Safety Reports From VigiBase

    NARCIS (Netherlands)

    Kroeger, Edeltraut; Mouls, Marie; Wilchesky, Machelle; Berkers, Mieke; Carmichael, Pierre-Hugues; van Marum, Rob; Souverein, Patrick; Egberts, Toine; Laroche, Marie-Laure

    2015-01-01

    Background: No worldwide pharmacovigilance study evaluating the spectrum of adverse drug reactions (ADRs) induced by cholinesterase inhibitors (ChEI) in Alzheimer's disease has been conducted since their emergence on the market. Objective: To describe ChEI related ADRs in Alzheimer's disease

  7. Adverse Drug Reactions Reported With Cholinesterase Inhibitors : An Analysis of 16 Years of Individual Case Safety Reports From VigiBase

    NARCIS (Netherlands)

    Kröger, Edeltraut; Mouls, Marie; Wilchesky, Machelle; Berkers, Mieke; Carmichael, Pierre-Hugues; van Marum, Rob; Souverein, Patrick; Egberts, Toine; Laroche, Marie-Laure

    2015-01-01

    BACKGROUND: No worldwide pharmacovigilance study evaluating the spectrum of adverse drug reactions (ADRs) induced by cholinesterase inhibitors (ChEI) in Alzheimer's disease has been conducted since their emergence on the market. OBJECTIVE: To describe ChEI related ADRs in Alzheimer's disease

  8. Impact of cholinesterase inhibitors on behavioral and psychological symptoms of Alzheimer’s disease: A meta-analysis

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    Noll Campbell

    2008-12-01

    Full Text Available Noll Campbell1, Amir Ayub2, Malaz A Boustani2, Chris Fox3, Martin Farlow4, Ian Maidment3, Robert Howard51Wishard Health Services, Indianapolis, Indiana; 2Indiana University Center for Aging Research, Regenstrief Institute, Inc., Indianapolis, Indiana; 3University of Kent, Kent, United Kingdom; 4Indiana University School of Medicine, Indianapolis, Indiana; 5King’s College, London, United KingdomObjective: To determine the efficacy of cholinesterase inhibitors (ChEIs in improving the behavioral and psychological symptoms of dementia (BPSD in patients with Alzheimer’s disease (AD.Data sources: We searched MEDLINE, Cochrane Registry, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL from 1966 to 2007. We limited our search to English Language, full text, published articles and human studies.Data extraction: We included randomized, double-blind, placebo-controlled trials evaluating the efficacy of donepezil, rivastigmine, or galantamine in managing BPSD displayed by AD patients. Using the United States Preventive Services Task Force (USPSTF guidelines, we critically appraised all studies and included only those with an attrition rate of less than 40%, concealed measurement of the outcomes, and intention to treat analysis of the collected data. All data were imputed into pre-defined evidence based tables and were pooled using the Review Manager 4.2.1 software for data synthesis.Results: We found 12 studies that met our inclusion criteria but only nine of them provided sufficient data for the meta-analysis. Among patients with mild to severe AD and in comparison to placebo, ChEIs as a class had a beneficial effects on reducing BPSD with a standard mean difference (SMD of −0.10 (95% confidence interval [CI]; −0.18, −0.01 and a weighted mean difference (WMD of −1.38 neuropsychiatry inventory point (95% CI; −2.30, −0.46. In studies with mild AD patients, the WMD was −1.92 (95% CI; −3.18, −0.66; and in studies

  9. Effect of Part D coverage restrictions for antidepressants, antipsychotics, and cholinesterase inhibitors on related nursing home resident outcomes.

    Science.gov (United States)

    Stevenson, David G; O'Malley, A James; Dusetzina, Stacie B; Mitchell, Susan L; Zarowitz, Barbara J; Chernew, Michael E; Newhouse, Joseph P; Huskamp, Haiden A

    2014-09-01

    In 2006, Medicare Part D transitioned prescription drug coverage for dual-eligible nursing home residents from Medicaid to Medicare and randomly assigned them to Part D prescription drug plans (PDPs). Because PDPs may differ in coverage, plans may be more or less generous for drugs that an individual is taking. Taking advantage of the fact that randomization mitigates potential selection bias common in observational studies, this study sought to assess the effect of PDP coverage on resident outcomes for three medication classes--antidepressants, antipsychotics, and cholinesterase inhibitors. Retrospective cohort study to examine the effect of coverage restrictions--including noncoverage and coverage with restrictions--on depression, hallucinations and delusions, aggressive behaviors, cognitive performance, and activities of daily living for dual-eligible nursing home residents randomized to PDPs in 2006 to 2008. The analyses further adjusted for baseline health status to address any residual imbalances in the comparison groups. Linked data from Medicare claims, Minimum Data Set assessments, pharmacy claims, and PDP formulary information. Dual-eligible nursing home residents aged 65 and older living in facilities that contracted with a single pharmacy provider. PDP coverage restrictions in three medication classes of interest were not significantly associated with the resident outcomes examined. Although cholinesterase inhibitor users facing coverage restrictions had a 0.04-point lower depression rating score than residents facing no restrictions, this difference was not statistically significant after adjusting for multiple comparisons. The findings suggest that exogenous changes in coverage for three commonly used medication classes had no detectable effect on nursing home resident outcomes in 2006 to 2008. There are several possible explanations for this lack of association, including the role of policy protections for dual-eligible nursing home residents and the

  10. Cholinesterase inhibitors from Sargassum and Gracilaria gracilis: seaweeds inhabiting South Indian coastal areas (Hare Island, Gulf of Mannar).

    Science.gov (United States)

    Natarajan, Suganthy; Shanmugiahthevar, Karutha Pandian; Kasi, Pandima Devi

    2009-01-01

    Dementia is a chronic progressive mental disorder, which adversely affects memory, thinking, comprehension, calculation and language. Some of the commonest forms of dementia are Alzheimer's disease, Parkinsonism, Dementia with Lewy Bodies and Myasthenia gravis. All these disorders are related to abnormalities in the central cholinergic system, which shows a decline in acetylcholine level. Cholinesterase (ChE) inhibitors are one of the novel strategies used for the symptomatic treatment of neurological disorders like dementia. In the course of screening new ChE inhibitors from marine sources, about 11 seaweeds, which have wide pharmaceutical applications, were collected from Hare Island, Gulf of Mannar, Tamilnadu, India. Methanolic extracts of the seaweeds were assessed for ChE inhibitory activity under in vitro conditions. Kinetic parameters IC(50), K(i) and V(max) were also analysed. The results showed that 3/11 seaweeds showed 50% inhibition for both ChEs (using acetylthiocholine iodide and butyrylthiocholine iodide as substrate) at concentrations of 2 mg mL(-1) (Gracilaria gracilis, Sargassum, Cladophora fasicularis for ChE with acetylthiocholine iodide as substrate and Gracilaria gracilis, Gracilaria edulis, Sargassum for ChE with butyrylthiocholine iodide as substrate) and 4/11 showed no inhibitory activity. Inhibitory activity of seaweed extracts was compared with standard drug donepezil. Enzyme kinetic analysis showed that algal extracts exhibited mixed type inhibition (partially non-competitive inhibition).

  11. Rational choice of cholinesterase inhibitor for the treatment of Alzheimer's disease in Canada: a comparative economic analysis

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    Getsios Denis

    2003-12-01

    Full Text Available Abstract Background Cholinesterase inhibitors, such as galantamine, donepezil and rivastigmine are approved for symptomatic treatment of Alzheimer's Disease (AD in Canada. In making choices amongst these drugs, one should consider their clinical merits and their economic implications. Methods Each drug's short-term efficacy was estimated based on independent Cochrane reviews of the clinical trials. Long-term clinical and economic outcomes were estimated using the Assessment of Health Economics in Alzheimer's Disease (AHEAD model. Results While all treatments reduced the need for full-time care, only galantamine and donepezil 10 mg reduced the overall management costs of AD patients. The somewhat greater cognitive effect provided over six months by galantamine leads to the longest estimated delay before full-time care is required and, consequently to lower overall costs, with savings estimated at between $323 and $4,246. Conclusion Although there is uncertainty in estimated results, the best information currently available suggests that the first choice for treatment of AD should be galantamine. These results should be interpreted with caution, however, as results are not based on direct comparisons among the drugs and the differences emerging from meta-analyses of the trials are relatively small.

  12. Change in Odor Identification Impairment is Associated with Improvement with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment.

    Science.gov (United States)

    Devanand, D P; Lentz, Cody; Chunga, Richard E; Ciarleglio, Adam; Scodes, Jennifer M; Andrews, Howard; Schofield, Peter W; Stern, Yaakov; Huey, Edward D; Bell, Karen; Pelton, Gregory H

    2017-01-01

    Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease pathology. To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI). At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks. In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p < 0.03). This effect remained after adjusting for time, age, education, gender, APOE ɛ4 status, and baseline cognitive score (p < 0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (p < 0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (p = 0.07). Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment.

  13. 1,8-Naphthyridine derivatives as cholinesterases inhibitors and cell Ca2+ regulators, a multitarget strategy for Alzheimer's disease.

    Science.gov (United States)

    Egea, Javier; de los Rios, Cristobal

    2011-11-01

    The synthesis and the pharmacological evaluation of 1,8-naphthyridine derivatives and related compounds as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as voltage-dependant Ca(2+) channels (VDCC) modulators of are summarized. These compounds are closely related to the anticholinesterasic tacrine and the well-known Ca(2+)-antagonists 1,4-dihydropyridines. They were obtained from polyfunctionalized 2-amino-3-cyanoheterocycles via Friedlander-type reaction with selected cycloalkanones. Most of the compounds showed moderate inhibitory activity of cholinesterases, with selectivity to the AChE inhibition, and blocked Ca(2+) channels, preferentially the L-subtype, when a 4-aryl-1,4-DHP-like moiety were present in its chemical structure. Taking into account that the regulation of Ca(2+) entry to cells has been described to play a key role in cell death/survival processes, some of them were studied as cytoprotective agentes against different toxic stimuli. Specifically, the 1,8-naphthyridine derivative 30 was described to exert a tiny positive effect on Ca(2+) entry to cells, as single cell, isolated organ, and (45)Ca(2+) uptake experiments showed. This slight "Ca(2+)-promoter" behavior was related to its cytoprotective effect against several toxic stimuli, as Ca(2+)-chelating and antiapoptotic protein Bcl-2 was overexpressed in bovine chromaffin cells preincubated with 30. In fact, the relationship between small elevations of [Ca(2+)](c) and neuroprotection has been deeply studied by our group and others, concluding that a huge blockade of Ca(2+) entry does not have to generate neuroprotection, but the precise regulation, up or down, of such [Ca(2+)] concentrations. © 2011 Bentham Science Publishers

  14. Effects of Gingko biloba supplementation in Alzheimer's disease patients receiving cholinesterase inhibitors: data from the ICTUS study.

    Science.gov (United States)

    Canevelli, Marco; Adali, Nawal; Kelaiditi, Eirini; Cantet, Christelle; Ousset, Pierre-Jean; Cesari, Matteo

    2014-05-15

    Ginkgo biloba (Gb) is currently the most investigated and adopted herbal remedy for cognitive disorders and Alzheimer's disease (AD). Nevertheless, its efficacy in the prevention and treatment of dementia still remains controversial. Specifically, the added effects of Gb in subjects already receiving "conventional" anti-dementia treatments have been to date very scarcely investigated. We evaluated whether the use of Gb is associated with additional cognitive and functional benefit in AD patients already in treatment with cholinesterase inhibitors (ChEIs). Data are from mild to moderate AD patients under ChEI treatment recruited in the Impact of Cholinergic Treatment USe (ICTUS) study. Mixed model analyses were performed to measure six-monthly modifications in the Mini Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score, and the Activities of Daily Living (ADL) scale over a follow-up of 1 year according to the additional Gb supplementation. A total of 828 subjects were considered for the present analyses. Significantly different modifications at the MMSE score over the 12-month follow-up were reported between patients on combined therapy compared to those only taking ChEIs. On the contrary, the modification of the ADAS-Cog score between the two groups did not show statistically significant differences, although similar trends were noticed. No significant modifications of the two adopted outcome measures were observed at the mid-term 6-month evaluation. The modifications over time of the ADL score did not show statistically significant differences between the two groups of interest. Our findings suggest that Gb may provide some added cognitive benefits in AD patients already under ChEIs treatment. The clinical meaningfulness of such effects remains to be confirmed and clarified. Copyright © 2014 Elsevier GmbH. All rights reserved.

  15. Cholinesterase inhibitor and N-methyl-D-aspartic acid receptor antagonist use in older adults with end-stage dementia: a survey of hospice medical directors.

    Science.gov (United States)

    Shega, Joseph W; Ellner, Lynn; Lau, Denys T; Maxwell, Terri L

    2009-09-01

    Cholinesterase inhibitors and N-methyl-D-aspartic acid (NMDA) receptor antagonists are Food and Drug Administration (FDA) approved for the treatment of moderate to severe Alzheimer's disease. As dementia progresses to the end stage and patients become hospice-eligible, clinicians consider whether or not to continue these therapies without the benefit of scientific evidence. We sought to describe hospice medical directors practice patterns and experiences in the use and discontinuation of cholinesterase inhibitors and NMDA receptor antagonists in hospice patients that meet the Medicare hospice criteria for dementia. Mail survey of hospice medical directors from a random sample from the National Hospice and Palliative Care Organization. Of the 413 eligible participants, 152 completed surveys were returned, yielding a response rate of 37%. Of the respondents, 75% and 33% reported that at least 20% of their patients were taking a cholinesterase inhibitor or memantine, respectively, at the time of hospice admission. The majority of respondents do not consider these therapies effective in persons with end-stage dementia, however, a subset believe that these medications improved patient outcomes including stabilization of cognition (22%), decrease in challenging behaviors (28%), and maintenance of patient function (22%) as well as caregiver outcomes namely reduced caregiver burden (20%) and improved caregiver quality of life (20%). While 80% of respondents recommended discontinuing these therapies to families at the time of hospice enrollment, 72% of respondents reported that families experienced difficulty stopping these therapies. A subset of respondents observed accelerated cognitive (30%) and functional decline (26%) or emergence of challenging behaviors (32%) with medication discontinuation. The findings from this survey indicate that cholinesterase inhibitors and/or NMDA receptor antagonists are prescribed for a subset of patients with advanced dementia and that a

  16. Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil.

    Science.gov (United States)

    van Greunen, Divan G; Cordier, Werner; Nell, Margo; van der Westhuyzen, Chris; Steenkamp, Vanessa; Panayides, Jenny-Lee; Riley, Darren L

    2017-02-15

    A series of twenty seven acetylcholinesterase inhibitors, as potential agents for the treatment of Alzheimer's disease, were designed and synthesised based upon previously unexplored chemical space surrounding the molecular skeleton of the drug donepezil, which is currently used for the management of mild to severe Alzheimer's disease. Two series of analogues were prepared, the first looking at the replacement of the piperidine ring in donepezil with different sized saturated N-containing ring systems and the second looking at the introduction of different linkers between the indanone and piperidine rings in donepezil. The most active analogue 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (67) afforded an in vitro IC50 value of 0.03 ± 0.07 μM against acetylcholinesterase with no cytotoxicity observed (IC50 of >100 μM, SH-SY5Y cell line). In comparison donepezil had an IC50 of 0.05 ± 0.06 μM and an observed cytotoxicity IC50 of 15.54 ± 1.12 μM. Molecular modelling showed a strong correlation between activity and in silico binding in the active site of acetylcholinesterase. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. A Randomized Placebo-Controlled Discontinuation Study of Cholinesterase Inhibitors in Institutionalized Patients With Moderate to Severe Alzheimer Disease.

    Science.gov (United States)

    Herrmann, Nathan; O'Regan, Jordana; Ruthirakuhan, Myuri; Kiss, Alexander; Eryavec, Goran; Williams, Evelyn; Lanctôt, Krista L

    2016-02-01

    Cholinesterase inhibitors (ChEIs) offer modest benefits in Alzheimer disease (AD), which must be balanced against risks. Relatively few data delineate the benefits and risks of long-term ChEI administration in institutionalized patients with advanced AD. This study investigated the effects of ChEI discontinuation in institutionalized patients with AD. Institutionalized patients with moderate to severe AD (standardized Mini- Mental Status Examination ≤15) and treated with a ChEI for ≥2 years were randomized, double-blind, to ChEI continuation or placebo, with a 2-week tapering phase, for 8-weeks. The primary outcome of this pilot study was change on the Clinician's Global Impression of Change (CGI-C) scale. Secondary outcomes included safety, efficacy, and tolerability. Baseline (BL) predictors of clinical deterioration were also determined. Forty patients (mean ± standard deviation age = 89.3 ± 3.5 years, standardized Mini-Mental Status Examination = 8.1 ± 5.2, Neuropsychiatric Inventory-Nursing Home version total score = 21.1 ± 15.9, 80% male) were randomized to ChEI continuation (n = 21) or placebo (n = 19). There was no significant difference in clinical worsening in the ChEI continuation (28.6%) and placebo groups (36.8%) on CGI-C (odds ratio for worsening 1.58, 95% confidence interval .38-6.55, P = .53). The occurrence of adverse events was similar in both groups. There were no significant differences in any of the secondary outcome measures. In the placebo group, BL hallucinations predicted CGI-C worsening [F(1,17) = 6.4, P = .02], and there was a trend for BL delusions to predict CGI-C worsening [F(1,15) = 3.5, P = .08]. These results suggest that ChEI discontinuation is safe and well tolerated in the majority of institutionalized patients with moderate to severe AD. When discontinuing ChEI, the presence of hallucinations and delusions may predict clinical deterioration, suggesting the need for increased caution

  18. Scale Alpha and Beta of Quantitative Convergence and Chemical Reactivity Analysis in Dual Cholinesterase/Monoamine Oxidase Inhibitors for the Alzheimer Disease Treatment Using Density Functional Theory (DFT

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    Alejandro Morales-Bayuelo

    2013-01-01

    Full Text Available Molecular quantum similarity descriptors and Density Functional Theory (DFT based reactivity descriptors were studied for a series of cholinesterase/monoamine oxidase inhibitors used for the Alzheimer's disease treatment (AD. This theoretical study is expected to shed some light onto some molecular aspects that could contribute to the knowledge of the molecular mechanics behind interactions of these molecules with acetylcholinesterase (AChE and butyrylcholinesterase (BuChE, as well as with monoamine oxidase (MAO A and B. The Topogeometrical Superposition Algorithm to handle flexible molecules (TGSA-Flex alignment method was used to solve the problem of the relative orientation in the quantum similarity (QS field. Using the molecular quantum similarity (MQS field and reactivity descriptors supported in the DFT was possible the quantification of the steric and electrostatic effects through of the Coulomb and Overlap quantitative convergence scales (alpha and beta. In addition, an analysis of reactivity indexes is development, using global and local descriptors, identifying the binding sites and selectivity in the (cholinesterase/monoamine oxidase inhibitors, understanding the retrodonor process, and showing new insight for drugs design in a disease of difficult control as Alzheimer.

  19. Effect of discontinuing cholinesterase inhibitor therapy on behavioral and mood symptoms in nursing home patients with dementia.

    Science.gov (United States)

    Daiello, Lori A; Ott, Brian R; Lapane, Kate L; Reinert, Steven E; Machan, Jason T; Dore, David D

    2009-04-01

    Cholinesterase inhibitors (CHEIs) ameliorate some types of behavioral symptoms in patients with Alzheimer's disease. However, there has been little previous study of the outcomes associated with discontinuing these medications. The primary aim of this study was to evaluate the extent to which discontinuing CHEI therapy affected behavioral and mood symptoms in a cohort of nursing home residents with a diagnosis of dementia compared with residents receiving longer-term CHEI therapy. This was a retrospective cohort study using Rhode Island Medicaid prescription claims and the Minimum Data Set (MDS). Participants were Rhode Island nursing home residents aged > or =60 years with a diagnosis of Alzheimer's disease or non-Alzheimer's dementia, treated with CHEI monotherapy, and enrolled in the Medicaid program between January 1, 2004, and December 31, 2005. The discontinuation cohort (CHEI-DC) was selected by identifying residents who received 3 to 9 months of uninterrupted CHEI therapy. The continuation cohort (CHEI-CONT) was prescribed continuous CHEI therapy for >9 months. Changes in scores on the Aggressive Behavior Scale (ABS) and the Depression Rating Scale (DRS) for CHEI-DC residents were compared with changes in scores for CHEI-CONT residents. Secondary outcomes included change over time for individual behavioral symptoms and indicators of cognitive and functional status coded on the MDS. The final matched sample (N = 178) included 62 CHEI-DC cases and 116 CHEI-CONT controls. More than half of the cohort was aged > or =85 years, and the sample was predominantly female. A diagnosis of Alzheimer's disease was documented in 40.3% of the CHEI-DC patients and in 46.5% of the CHEI-CONT patients. Behavioral worsening, indicated by an increase in the estimated mean monthly point change in ABS score, occurred in the CHEI-DC group (0.08; 95% CI, 0.01 to 0.16) but not in the CHEI-CONT group (-0.01; 95% CI, -0.06 to 0.04), and the between-group difference was significant (0

  20. Reassessment of the dementia diagnosis of Alzheimer's disease in patients enrolled on the cholinesterase inhibitors dispensation program

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    Magda Cristina Flaitt Sanches Piovesana

    Full Text Available ABSTRACT Objective: Reassess the diagnosis of Alzheimer's Disease (AD in patients treated with anti-cholinesterases dispensed by High Cost Drug stores (Exceptional Drugs Program. Methods: A prospective study to reassess the diagnosis of probable Alzheimer's Disease was conducted (AD. The patients were submitted to the protocol of dementia investigation at the Neurogeriatric Outpatient Clinic of the Teaching Hospital de Base de São José do Rio Preto. Groups were classified using the criteria of the National Institute of Neurologic and Communicative Diseases and Vascular Cerebral Accident and Alzheimer Disease Related Association (NINCDS-ADRDA. The study was completed by applying the Disability Assessment for Dementia (DAD. The significance level was set at 5%. Results: 106 patients participated, selected randomly from a group of 390 patients contacted when receiving their medication at the High Cost Drug store. Two groups were formed: the first, containing 52 patients who fulfilled criteria for AD (FC Group; and a second, with 54 patients not fulfilling criteria (NFC. The FC Group had older age, worse performance on the Mini-Mental State Exam (MMSE and poorer performance on the DAD. Also, treatment time was longer and drugs doses higher in the FC Group. Conclusion: Study results showed a high number of patients using anti-cholinesterases that did not fulfill the diagnosis criteria for probable AD. Comparison of the two groups revealed different behavior between them, corroborating the hypothesis of inadequate inclusion of the NFC Group patients in the Exceptional Drugs Program.

  1. Design and Synthesis of New Dual Binding Site Cholinesterase Inhibitors: in vitro Inhibition Studies with in silico Docking.

    Science.gov (United States)

    Yar, Muhammad; Bajda, Marek; Mehmood, Rana Atif; Sidra, Lala Rukh; Ullah, Nisar; Shahzadi, Lubna; Ashraf, Muhammad; Ismail, Tayaba; Shahzad, Sohail Anjum; Khan, Zulfiqar Ali; Naqvi, Syed Ali Raza; Mahmood, Nasir

    2014-03-01

    Cholinesterases (ChEs) play a vital role in the regulation of cholinergic transmission. The inhibition of ChEs is considered to be involved in increasing acetylcholine level in the brain and thus has been implicated in the treatment of Alzheimer's disease. We have designed and synthesized a series of novel indole derivatives and screened them for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Most of the tested compounds exhibited inhibitory activity against AChE and BChE. Among them 4f and 6e showed the highest AChE inhibitory activity with IC50 91.21±0.06 and 68.52±0.04 μM, respectively. However compound 5a exhibited the highest inhibitory activity against BChE (IC50 55.21±0.12 μM).

  2. Resistance to inhibitors of cholinesterase (Ric-8A and Gαi contribute to cytokinesis abscission by controlling vacuolar protein-sorting (Vps34 activity.

    Directory of Open Access Journals (Sweden)

    Cedric Boularan

    Full Text Available Resistance to inhibitors of cholinesterase (Ric-8A is a guanine nucleotide exchange factor for Gαi, Gαq, and Gα12/13, which is implicated in cell signaling and as a molecular chaperone required for the initial association of nascent Gα subunits with cellular membranes. Ric-8A, Gαi subunits, and their regulators are localized at the midbody prior to abscission and linked to the final stages of cell division. Here, we identify a molecular mechanism by which Ric-8A affects cytokinesis and abscission by controlling Vps34 activity. We showed that Ric-8A protein expression is post-transcriptionally controlled during the cell cycle reaching its maximum levels at mitosis. A FRET biosensor created to measure conformational changes in Ric-8A by FLIM (Fluorescence Lifetime Imaging Microscopy revealed that Ric-8A was in a close-state during mitosis and particularly so at cytokinesis. Lowering Ric-8A expression delayed the abscission time of dividing cells, which correlated with increased intercellular bridge length and multinucleation. During cytokinesis, Ric-8A co-localized with Vps34 at the midbody along with Gαi and LGN, where these proteins functioned to regulate Vps34 phosphatidylinositol 3-kinase activity.

  3. Resistance to inhibitors of cholinesterase (Ric)-8A and Gαi contribute to cytokinesis abscission by controlling vacuolar protein-sorting (Vps)34 activity.

    Science.gov (United States)

    Boularan, Cedric; Kamenyeva, Olena; Cho, Hyeseon; Kehrl, John H

    2014-01-01

    Resistance to inhibitors of cholinesterase (Ric)-8A is a guanine nucleotide exchange factor for Gαi, Gαq, and Gα12/13, which is implicated in cell signaling and as a molecular chaperone required for the initial association of nascent Gα subunits with cellular membranes. Ric-8A, Gαi subunits, and their regulators are localized at the midbody prior to abscission and linked to the final stages of cell division. Here, we identify a molecular mechanism by which Ric-8A affects cytokinesis and abscission by controlling Vps34 activity. We showed that Ric-8A protein expression is post-transcriptionally controlled during the cell cycle reaching its maximum levels at mitosis. A FRET biosensor created to measure conformational changes in Ric-8A by FLIM (Fluorescence Lifetime Imaging Microscopy) revealed that Ric-8A was in a close-state during mitosis and particularly so at cytokinesis. Lowering Ric-8A expression delayed the abscission time of dividing cells, which correlated with increased intercellular bridge length and multinucleation. During cytokinesis, Ric-8A co-localized with Vps34 at the midbody along with Gαi and LGN, where these proteins functioned to regulate Vps34 phosphatidylinositol 3-kinase activity.

  4. The effect of APOE ε4 allele on cholinesterase inhibitors in patients with Alzheimer disease: evaluation of the feasibility of resting state functional connectivity magnetic resonance imaging.

    Science.gov (United States)

    Wang, Liang; Day, Jonathan; Roe, Catherine M; Brier, Matthew R; Thomas, Jewell B; Benzinger, Tammie L; Morris, John C; Ances, Beau M

    2014-01-01

    This work is to determine whether apolipoprotein E (APOE) genotype modulates the effect of cholinesterase inhibitor (ChEI) treatment on resting state functional connectivity magnetic resonance imaging (rs-fcMRI) in patients with Alzheimer disease (AD). We retrospectively studied very mild and mild AD participants who were treated (N=25) or untreated (N=19) with ChEIs with respect to rs-fcMRI measure of 5 resting state networks (RSNs): default mode, dorsal attention (DAN), control (CON), salience (SAL), and sensory motor. For each network, a composite score was computed as the mean of Pearson correlations between pairwise time courses extracted from areas comprising this network. The composite scores were analyzed as a function of ChEI treatment and APOE ε4 allele. Across all participants, significant interactions between ChEI treatment and APOE ε4 allele were observed for all 5 RSNs. Within APOE ε4 carriers, significantly greater composite scores were observed in the DAN, CON, and SAL for treated compared with untreated participants. Within APOE ε4 noncarriers, treated and untreated participants did not have significantly different composite scores for all RSNs. These data suggest that APOE genotype affects the response to ChEI using rs-fcMRI. Rs-fcMRI may be useful for assessing the therapeutic effect of medications in AD clinical trials.

  5. Memantine treatment in patients with mild to moderate Alzheimer's disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Porsteinsson, Anton P; Grossberg, George T; Mintzer, Jacobo; Olin, Jason T

    2008-02-01

    To evaluate the efficacy and safety of memantine in patients with mild to moderate Alzheimer's disease (AD) receiving cholinesterase inhibitor (ChEI) treatment. Participants (N= 433) with probable AD, Mini-Mental State Exam (MMSE) scores between 10-22 (inclusive), and concurrent stable use of ChEIs (donepezil, rivastigmine, galantamine) were randomized to placebo or memantine (20 mg once daily) for 24 weeks. Primary outcomes were changes from baseline on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and on Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) score. Secondary measures comprised the 23-item Alzheimer Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL(23)), Neuropsychiatric Inventory (NPI), and MMSE. At the end of the trial, there were no statistically significant differences between the memantine- and placebo group on primary and secondary outcome measures. The incidence of adverse events (AEs) was similar between the two groups, with no AE occurring in more than 5% of memantine-treated patients and at a rate twice that of the placebo group. In this trial, memantine did not show an advantage over placebo based on protocol-specified primary or secondary analyses in patients with mild to moderate AD on stable ChEI regimens. There were no significant differences in tolerability and safety between the memantine- and placebo groups.

  6. Testing Van Gool’s Hypothesis: A Method to Predict Side Effects of Cholinesterase Inhibitors in Patients with Cellular Degenerative and Vascular Dementia

    Directory of Open Access Journals (Sweden)

    Liza van Eijk

    2015-01-01

    Full Text Available This study investigates a method to predict medical outcome of cholinesterase inhibitors in patients with Alzheimer’s disease (AD and vascular dementia (VaD. Van Gool predicts that patients with cholinergic deficit symptoms will benefit from treatment whereas patients without will experience side effects because of overstimulation of the cholinergic system. We predicted that AD and VaD patients with a longer RT experience fewer side effects than patients with a faster response and that VaD patients have a longer RT than AD patients. A number of 71 patients with AD or VaD diagnosis were included. A sustained attention task was administered, as well as the MMSE and a questionnaire about side effects. Results indicated that VaD patients with a longer RT reported fewer side effects. Furthermore, patients with VaD had a longer RT than patients with AD. MMSE was negatively correlated with RT in the VaD group. Thus, the performance on the attention task seems associated with suffering from side effects and thus tends to predict medical outcome in VaD, but not in AD. Perhaps this attention task was not sensitive enough to measure cholinergic deficit symptoms in AD patients. Furthermore, different doses of medication might confound the effect for the AD group.

  7. A longitudinal study of risk factors for community-based home help services in Alzheimer’s disease: the influence of cholinesterase inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Wattmo C

    2013-03-01

    Full Text Available Carina Wattmo, Elisabeth Paulsson, Lennart Minthon, Elisabet LondosClinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Malmö, SwedenBackground: To investigate the long-term effects of cholinesterase inhibitor (ChEI therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS by patients with Alzheimer’s disease (AD.Methods: This 3-year, prospective, multicenter study included 880 AD patients treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every 6 months, the patients were assessed with several rating scales, including the Mini-Mental State Examination, Instrumental Activities of Daily Living (IADL, and Physical Self-Maintenance Scale. Doses of ChEI and amounts of HHS per week were recorded. Cox regression models were used to predict the time to HHS, and multiple linear regression was used to predict the volume of HHS used.Results: During the study, 332 patients (38% used HHS. Factors that both postponed HHS use and predicted lower amounts of HHS were higher doses of ChEIs, better IADL ability, and living with family. Men, younger individuals, and those with a slower IADL decline showed a longer time to HHS, whereas female sex, a lower cognitive status, or more medications at baseline predicted fewer hours of HHS.Conclusions: Higher doses of ChEI might reduce the use of HHS, possibly reducing the costs of community-based care. Female spouses provide more informal care than do male spouses, so the likelihood of using HHS is greater among women with AD. The "silent group" of more cognitively impaired and frail elderly AD patients receives less HHS, which might precipitate institutionalization.Keywords: cognition, activities of daily living, treatment effect, gender, predictors

  8. A longitudinal study of risk factors for community-based home help services in Alzheimer's disease: the influence of cholinesterase inhibitor therapy.

    Science.gov (United States)

    Wattmo, Carina; Paulsson, Elisabeth; Minthon, Lennart; Londos, Elisabet

    2013-01-01

    To investigate the long-term effects of cholinesterase inhibitor (ChEI) therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS) by patients with Alzheimer's disease (AD). This 3-year, prospective, multicenter study included 880 AD patients treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every 6 months, the patients were assessed with several rating scales, including the Mini-Mental State Examination, Instrumental Activities of Daily Living (IADL), and Physical Self-Maintenance Scale. Doses of ChEI and amounts of HHS per week were recorded. Cox regression models were used to predict the time to HHS, and multiple linear regression was used to predict the volume of HHS used. During the study, 332 patients (38%) used HHS. Factors that both postponed HHS use and predicted lower amounts of HHS were higher doses of ChEIs, better IADL ability, and living with family. Men, younger individuals, and those with a slower IADL decline showed a longer time to HHS, whereas female sex, a lower cognitive status, or more medications at baseline predicted fewer hours of HHS. Higher doses of ChEI might reduce the use of HHS, possibly reducing the costs of community-based care. Female spouses provide more informal care than do male spouses, so the likelihood of using HHS is greater among women with AD. The "silent group" of more cognitively impaired and frail elderly AD patients receives less HHS, which might precipitate institutionalization.

  9. Kinetics and molecular docking studies of cholinesterase inhibitors derived from water layer of Lycopodiella cernua (L.) Pic. Serm. (II).

    Science.gov (United States)

    Hung, Tran Manh; Lee, Joo Sang; Chuong, Nguyen Ngoc; Kim, Jeong Ah; Oh, Sang Ho; Woo, Mi Hee; Choi, Jae Sue; Min, Byung Sun

    2015-10-05

    Acetylcholinesterase (AChE) inhibitors increase the availability of acetylcholine in central cholinergic synapses and are the most promising drugs currently available for the treatment of Alzheimer's disease (AD). Our screening study indicated that the water fraction of the methanolic extract of Lycopodiella cernua (L.) Pic. Serm. significantly inhibited AChE in vitro. Bioassay-guided fractionation led to the isolation of a new lignan glycoside, lycocernuaside A (12), and fourteen known compounds (1-11 and 13-15). Compound 7 exhibited the most potent AChE inhibitory activity with an IC50 value of 0.23 μM. Compound 15 had the most potent inhibitory activity against BChE and BACE1 with IC50 values of 0.62 and 2.16 μM, respectively. Compounds 4 and 7 showed mixed- and competitive-type AChE inhibition. Compound 7 noncompetitively inhibited BChE whereas 15 showed competitive and 8, 13, and 14 showed mixed-type inhibition. The docking results for complexes with AChE or BChE revealed that inhibitors 4, 7, and 15 stably positioned themselves in several pocket/catalytic domains of the AChE and BChE residues. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Central Cholinesterase Inhibition Enhances Glutamatergic Synaptic Transmission

    OpenAIRE

    Kozhemyakin, Maxim; Rajasekaran, Karthik; Kapur, Jaideep

    2010-01-01

    Central cholinergic overstimulation results in prolonged seizures of status epilepticus in humans and experimental animals. Cellular mechanisms of underlying seizures caused by cholinergic stimulation remain uncertain, but enhanced glutamatergic transmission is a potential mechanism. Paraoxon, an organophosphate cholinesterase inhibitor, enhanced glutamatergic transmission on hippocampal granule cells synapses by increasing the frequency and amplitude of spontaneous excitatory postsynaptic cu...

  11. Pulmonary Toxicity of Cholinesterase Inhibitors

    Science.gov (United States)

    2006-01-01

    following: (1) parasympathetic muscarinic effects lead- believe that Hitler, a victim of a chlorine gas attack during ing to increased glandular...appearing early in thethis Ct for sarin can be attained with an exposure to a course of intoxication , was the first to disappear, and exer-concentration of 2...the signs route. In addition, respiratory symptoms of chest tightnessand symptoms observed after mild to moderate OP intox - were late appearing

  12. Assessing capacity to consent to treatment with cholinesterase inhibitors in dementia using a specific and standardized version of the MacArthur Competence Assessment Tool (MacCAT-T).

    Science.gov (United States)

    Mueller, Tanja; Haberstroh, Julia; Knebel, Maren; Oswald, Frank; Kaspar, Roman; Kemper, Christoph J; Halder-Sinn, Petra; Schroeder, Johannes; Pantel, Johannes

    2017-02-01

    The use of assessment tools has been shown to improve the inter-rater reliability of capacity assessments. However, instrument-based capacity assessments of people with dementia face challenges. In dementia research, measuring capacity with instruments like the MacArthur Competence Assessment Tool for Treatment (MacCAT-T) mostly employ hypothetical treatment vignettes that can overwhelm the abstraction capabilities of people with dementia and are thus not always suitable for this target group. The primary aim of this study was to provide a standardized real informed consent paradigm that enables the dementia-specific properties of capacity to consent to treatment in people with dementia to be identified in a real informed consent process that is both externally valid and ethically justifiable. The sample consisted of 53 people with mild to moderate dementia and a group of 133 people without cognitive impairment. Rather than using a hypothetical treatment vignette, we used a standardized version of the MacCAT-T to assess capacity to consent to treatment with cholinesterase inhibitors in people with dementia. Inter-rater reliability, item statistics, and psychometric properties were also investigated. Intraclass correlations (ICCs) (0.951-0.990) indicated high inter-rater reliability of the standardized real informed consent paradigm. In the dementia group, performance on different items of the MacCAT-T varied. Most people with dementia were able to express a treatment choice, and were aware of the need to take a tablet. Further information on the course of the disorder and the benefits and risks of the treatment were less understood, as was comparative reasoning regarding treatment alternatives. The standardized real informed consent paradigm enabled us to detect dementia-specific characteristics of patients' capacity to consent to treatment with cholinesterase inhibitors. In order to determine suitable enhanced consent procedures for this treatment, we recommend

  13. The effect of APOE ε4 allele on cholinesterase inhibitors in patients with Alzheimer’s disease: Evaluation of the feasibility of resting state functional connectivity magnetic resonance imaging

    Science.gov (United States)

    Wang, Liang; Day, Jonathan; Roe, Catherine M.; Brier, Matthew R.; Thomas, Jewell B.; Benzinger, Tammie L.; Morris, John C.; Ances, Beau M.

    2013-01-01

    This work is to determine whether apolipoprotein E (APOE) genotype modulates the effect of cholinesterase inhibitor (ChEI) treatment on resting state functional connectivity magnetic resonance imaging (rs-fcMRI) in patients with Alzheimer’s disease (AD). We retrospectively studied very mild and mild AD participants who were treated (N=25) or untreated (N=19) with ChEIs with respect to rs-fcMRI measure of 5 resting state networks (RSNs): default mode, dorsal attention (DAN), control (CON), salience (SAL), and sensory-motor. For each network, a composite score was computed as the mean of Pearson’s correlations between pairwise time courses extracted from areas comprising this network. The composite scores were analyzed as a function of ChEI treatment and APOE ε4 allele. Across all participants, significant interactions between ChEI treatment and APOE ε4 allele were observed for all 5 RSNs. Within APOE ε4 carriers, significantly greater composite scores were observed in the DAN, CON and SAL for treated compared to untreated participants. Within APOE ε4 non-carriers, treated and untreated participants did not have significantly different composite scores for all RSNs. These data suggest that APOE genotype affects the response to ChEI using rs-fcMRI. Rs-fcMRI may be useful for assessing the therapeutic effect of medications in AD clinical trials. PMID:24830360

  14. Depressão vascular no idoso: resposta ao tratamento antidepressivo associado a inibidor das colinesterases Vascular depression in elderly: response to treatment with antidepressant associated to cholinesterase inhibitor

    Directory of Open Access Journals (Sweden)

    Ricardo Barcelos

    2007-01-01

    Full Text Available CONTEXTO: Entre os transtornos neuropsiquiátricos ocasionados por eventos cerebrovasculares, a depressão vascular é pouco diagnosticada por médicos não especialistas, causando aumento da morbimortalidade de pacientes idosos. CASO CLÍNICO: Trata-se de um paciente com 67 anos que apresentou resposta parcial a tratamento com inibidores da recaptura de serotonina e efeitos adversos autonômicos graves com outros antidepressivos. A adição de rivastigmina ao citalopram promoveu sucesso terapêutico, com redução de 23 para 7 pontos, na escala de Hamilton para depressão. DISCUSSÃO: O resultado obtido traz novas perspectivas para o tratamento da depressão vascular, sendo necessários ensaios clínicos controlados que evidenciem o benefício da adição dos inibidores das colinesterases aos antidepressivos no tratamento destes pacientes.CONTEXT: Among neuropsychiatric disorders caused by cerebrovascular factors, vascular depression is diagnosed in a small degree by general practitioners, causing morbid-mortality increase in elderly. CASE REPORT: That is a case of a 67 year-old-man with partial response after treatment with a Selective Serotonin Receptors Inhibitor, and severe autonomic adverse effects with other antidepressants. The addition of rivastigmine to citalopram resulted in a therapeutic success, with a reduction of 23 to 7 points on the Hamilton Depressive Scale (HAM-D. DISCUSSION: The result obtained brings new perspectives to the treatment of vascular depression, providing that randomized controlled trials with larger sample sizes confirm the positive effect of the addition of a cholinesterase inhibitor to antidepressants in the treatment of these patients.

  15. Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Youssef Dgachi

    2016-05-01

    Full Text Available We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM, good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

  16. Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids

    Directory of Open Access Journals (Sweden)

    Bautista-Aguilera OM

    2014-10-01

    Full Text Available Oscar M Bautista-Aguilera,1,* Gerard Esteban,2,* Mourad Chioua,1 Katarina Nikolic,3 Danica Agbaba,3 Ignacio Moraleda,4 Isabel Iriepa,4 Elena Soriano,5 Abdelouahid Samadi,1 Mercedes Unzeta,2 José Marco-Contelles1 1Laboratory of Medicinal Chemistry (Institute of General Organic Chemistry [IQOG], National Research Council [CSIC], Madrid, Spain; 2Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Autonomous Barcelona University, Barcelona, Spain; 3Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia; 4Department of Organic Chemistry, Faculty of Pharmacy, University of Alcalá, Ctra Barcelona, Alcalá de Henares, Spain; 5Synthesis, and Structure of Organic Compounds (SEPCO (IQOG, CSIC, Madrid, Spain *These authors have equally contributed to this work Abstract: The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs as multipotent cholinesterase (ChE and monoamine oxidase (MAO inhibitors for the potential treatment of Alzheimer’s disease (AD is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE, and butyrylcholinesterase (BuChE enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (­Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE. Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for h

  17. Cholinesterase inhibitory activity of chlorophenoxy derivatives-Histamine H3 receptor ligands.

    Science.gov (United States)

    Łażewska, Dorota; Jończyk, Jakub; Bajda, Marek; Szałaj, Natalia; Więckowska, Anna; Panek, Dawid; Moore, Caitlin; Kuder, Kamil; Malawska, Barbara; Kieć-Kononowicz, Katarzyna

    2016-08-15

    In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer's disease. Combination of both: a histamine H3 receptor antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands-chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range. The most potent in this group was 1-(7-(4-chlorophenoxy)heptyl)homopiperidine (18) inhibiting the both enzymes (EeAChE IC50=1.93μM and EqBuChE IC50=1.64μM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H3 receptor as well as with cholinesterases. Copyright © 2016. Published by Elsevier Ltd.

  18. Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor ...

    African Journals Online (AJOL)

    Namibia is the driest sub-Saharan country in Africa. Namibia's capital, Windhoek, reclaims sewage water for domestic use at the Goreangab Water Reclamation Plant (GWRP). Risks associated with sewage effluent and reclaimed sewage should be closely monitored; therefore water at the Gammams Sewage Treatment ...

  19. New cholinesterase inhibitors from Garcinia atroviridis.

    Science.gov (United States)

    Tan, Wen-Nee; Khairuddean, Melati; Wong, Keng-Chong; Khaw, Kooi-Yeong; Vikneswaran, Murugaiyah

    2014-09-01

    A triflavanone, Garcineflavanone A (1) and a biflavonol, Garcineflavonol A (2) have been isolated from the stem bark of Garcinia atroviridis (Clusiaceae), collected in Peninsular Malaysia. Their structures were established using one and two-dimensional NMR, UV, IR and mass spectrometry and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibitory activity. Molecular docking studies of the isolated compounds were performed using docking procedure of AutoDock to disclose the binding interaction and orientation of these molecules into the active site gorge. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor ...

    African Journals Online (AJOL)

    2013-07-08

    Jul 8, 2013 ... removal during reclamation of sewage to drinking water. AK Faul1,2, E Julies1, and ... closely monitored; therefore water at the Gammams Sewage Treatment Plant (GSTP) inlet and outlet, as well as reclaimed water from the ... led to the upgrade of the conventional water treatment plant in the vicinity of the ...

  1. Evaluation of candidate genes for cholinesterase activity in farmworkers exposed to organophosphorus pesticides: association of single nucleotide polymorphisms in BCHE.

    Science.gov (United States)

    Howard, Timothy D; Hsu, Fang-Chi; Grzywacz, Joseph G; Chen, Haiying; Quandt, Sara A; Vallejos, Quirina M; Whalley, Lara E; Cui, Wei; Padilla, Stephanie; Arcury, Thomas A

    2010-10-01

    Organophosphate pesticides act as cholinesterase inhibitors. For those with agricultural exposure to these chemicals, risk of potential exposure-related health effects may be modified by genetic variability in cholinesterase metabolism. Cholinesterase activity is a useful, indirect measurement of pesticide exposure, especially in high-risk individuals such as farmworkers. To understand fully the links between pesticide exposure and potential human disease, analyses must be able to consider genetic variability in pesticide metabolism. We studied participants in the Community Participatory Approach to Measuring Farmworker Pesticide Exposure (PACE3) study to determine whether cholinesterase levels are associated with single-nucleotide polymorphisms (SNPs) involved in pesticide metabolism. Cholinesterase levels were measured from blood samples taken from 287 PACE3 participants at up to four time points during the 2007 growing season. We performed association tests of cholinesterase levels and 256 SNPs in 30 candidate genes potentially involved in pesticide metabolism. A false discovery rate (FDR) p-value was used to account for multiple testing. Thirty-five SNPs were associated (unadjusted p effect that is independent of pesticide exposure. Common genetic variation in the BCHE gene may contribute to subtle changes in cholinesterase levels.

  2. Design and Synthesis of Bifunctional Oxime Reactivators of OP- inhibited Cholinesterase

    Science.gov (United States)

    2013-08-01

    Oxime Reactivators of OP- inhibited Cholinesterases PRINCIPAL INVESTIGATOR: John T. Koh, Ph.D. CONTRACTING ORGANIZATION...Annual 3. DATES COVERED 08 August 2012-07 August 2013 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Design and synthesis of bifunctional oxime ...feasibly of synthesizing two new classes of oxime reactivators that use bifunctional catalysis to enhance kinetics and improve bioavailability. The

  3. Inhibitors

    Science.gov (United States)

    ... and exercise, immune tolerance therapy, and needs of older adults with hemophilia and an inhibitor. For more information, visit https://www.hemophilia.org/Events-Educational-Programs/Inhibitor-Education/Inhibitor-Education-Summits The NHF’s Inhibitor Education Summits ...

  4. Cholinesterases inhibition and molecular modeling studies of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones.

    Science.gov (United States)

    Shah, Muhammad Shakil; Khan, Shafi Ullah; Ejaz, Syeda Abida; Afridi, Saifullah; Rizvi, Syed Umar Farooq; Najam-Ul-Haq, Muhammad; Iqbal, Jamshed

    2017-01-22

    Super-activation of cholinesterases (acetylcholinesterase and butyrylcholinesterase) are linked to various neurological problems most precisely Alzheimer's disease (AD), which leads to senile dementia. Therefore, cholinesterases (AChE & BChE) inhibition are considered as a promising strategy for the treatment of Alzheimer's disease. FDA approved drugs for the treatment of AD, belong to a group of cholinesterase inhibitors. However, none of them is able to combat or completely abrogate the disease progression. Herein, we report a series of newly synthesized chalcone derivatives with anti-AD potential. For this purpose, a series of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones were tested for their cholinesterases (AChE & BChE) inhibitory activity. All compounds were found as selective inhibitor of AChE. In piperidyl chalcones derivatives compound 1e having IC50 of 0.16 ± 0.008 μM and 2m in 2-pyrazoline chalcones with IC50 of 0.13 ± 0.006 μM, were found to be the most potent inhibitors of AChE, exhibiting ≈142 and ≈ 173-fold greater inhibitory potential compared to the reference inhibitor i.e., Neostigmine (IC50 ± SEM = 22.2 ± 3.2 μM). Molecular docking studies of most potent inhibitors were carried out to investigate the binding interactions inside the active site. Molecular docking study revealed that potent compounds and co-crystalized ligand had same binding orientation within the active site of target enzyme. Most of these compounds are selective inhibitors of AChE with a potential use against progressive neurodegenerative disorder and age related problems. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Cholinesterase modulations in patients with acute bacterial meningitis

    DEFF Research Database (Denmark)

    Berg, Ronan M G; Ofek, Keren; Qvist, Tavs

    2011-01-01

    The circulating cholinesterases acetyl- and butyrylcholinesterase may be suppressed and subsequently released from the brain in acute bacterial meningitis.......The circulating cholinesterases acetyl- and butyrylcholinesterase may be suppressed and subsequently released from the brain in acute bacterial meningitis....

  6. Phosalone-Induced Changes in Regional Cholinesterase Activities ...

    African Journals Online (AJOL)

    Nekky Umera

    Abstract. Organophosphate pesticides exert their toxic effects by cholinesterase inhibition and the consequent prolongation of the undesirable effects of accumulation of acetylcholine. The signs of toxicity include tremors, convulsions, lachrymation, defecation etc. However, sustained cholinesterase inhibition through ...

  7. Biological Studies in Childhood Schizophrenia: Plasma and RBC Cholinesterase Activity

    Science.gov (United States)

    Lucas, Alexander R.; And Others

    1971-01-01

    A comparison of plasma (pseudo) cholinesterase and erythrocyte (true) cholinesterase activity in 16 male childhood schizophrenic patients and 16 male nonpsychotic hospitalized controls revealed no significant differences between the two groups. (Author)

  8. Cholinesterase inhibition improves blood flow in the ischemic cerebral cortex.

    Science.gov (United States)

    Scremin, O U; Li, M G; Scremin, A M; Jenden, D J

    1997-01-01

    The ability of central cholinesterase inhibition to improve cerebral blood flow in the ischemic brain was tested in Sprague-Dawley rats with tandem occlusion of left middle cerebral and common carotid arteries. Cerebral blood flow was measured with lodo- 14C-antipyrine autoradiography in 170 regions of cerebral cortex. The regional distribution of blood flow was characterized in normal animals by cerebral blood flow maxima in the temporal regions. After 2 h ischemia, minimum cerebral blood flow values were found in the lateral frontal and parietal areas on the left hemisphere, and a new maximum was found in the right hemisphere in an area approximately symmetrical to the ischemic focus. Heptyl-physostigmine (eptastigmine), a carbamate cholinesterase inhibitor with prolonged time of action improved cerebral blood flow in most regions, with the exception of the ischemic core. The drug also enhanced the ischemia-induced rostral shift of cerebral blood flow maxima in the right hemisphere. The effects of eptastigmine were more marked 24 h after ischemia. Discriminant analysis showed that data from only 22 regions was sufficient to achieve 100% accuracy in classifying all cases into the various experimental conditions. The redistribution of cerebral blood flow to the sensorimotor area of the right hemisphere of animals with cerebral ischemia, a phenomenon possibly related to recovery of function, was also enhanced by eptastigmine.

  9. Partial protection from organophosphate-induced cholinesterase inhibition by metyrapone treatment

    OpenAIRE

    Radosław Świercz; Piotr Lutz; Sławomir Gralewicz; Zofia Grzelińska; Joanna Piasecka-Zelga; Wojciech Wąsowicz

    2013-01-01

    Background: Organophosphates are cholinesterase (ChE) inhibitors with worldwide use as insecticides. Stress response, evidenced by a dramatic and relatively long-lasting (several hours) rise in the plasma glucocorticoid concentration is an integral element of the organophosphate (OP) poisoning symptomatology. In rodents, corticosterone (CORT) is the main glucocorticoid. There are several reports suggesting a relationship between the stressor-induced rise in CORT concentraion (the CORT respons...

  10. Reactivation of model cholinesterases by oximes and intermediate phosphyloximes: A computational study

    OpenAIRE

    Vyas, Shubham; Hadad, Christopher M.

    2008-01-01

    Phosphyloximes (POX) are generated upon the reactivation of organophosphorus (OP) inhibited cholinesterases (ChEs) by pyridinium oximes. These POXs are known to be potent inhibitors of the ChEs following reactivation. However, they can also decompose to give an OP derivative and a cyano derivative of the oxime when a base abstracts the benzylic proton. Using density functional theory, thermodynamic properties were calculated for the reactivation and decomposition pathways of three different o...

  11. Early appearance and possible roles of non-neuromuscular cholinesterases.

    Directory of Open Access Journals (Sweden)

    Carla eFalugi

    2012-04-01

    Full Text Available The biological function of the cholinesterase (ChE enzymes is well known and has been studied since the beginning of the XXth century; in particular, acetylcholinesterase (AChE, E.C. 3.1.1.7 is an enzyme playing a key role in the modulation of neuromuscular impulse transmission. However, in the past decades, there has been increasing interest concerning its role in regulating non-neuromuscular cell-to-cell interactions mediated by intracellular ion concentration changes, like the ones occurring during gamete interaction and embryonic development. An understanding of the mechanisms of the cholinergic regulation of these events can help us foresee the possible impact on environmental and human health, including gamete efficiency and possible teratogenic effects on different models, and help elucidate the extent to which exposure to ChE inhibitors may affect human health.

  12. Partial purification and properties of flyhead cholinesterase

    NARCIS (Netherlands)

    Dauterman, W.C.; Talens, A; Asperen, K. van

    Housefly head cholinesterase was purified using the following steps: (1) freeze-drying of flyheads, (2) solubilization of the enzyme by butanol extraction, (3) ammonium sulphate precipitation at pH 7, (4) heat denaturation of proteins in the presence of acetylcholine for protection of the

  13. MEASURING CHOLINESTERASE ACTIVITY IN HUMAN SALIVA.

    Science.gov (United States)

    To assess the potential for using saliva in pesticide biomonitoring, the consistency of cholinesterase activity in human saliva collected over time was examined. In this pilot study, saliva was collected from 20 healthy adults once per week for 5 consecutive weeks using 2 differe...

  14. Cholinesterase and self-reported pesticide exposure among pregnant women.

    Science.gov (United States)

    De Peyster, A; Willis, W O; Molgaard, C A; MacKendrick, T M; Walker, C

    1993-01-01

    Ascertainment of exposure to cholinesterase-inhibiting pesticides in pregnant subjects is complicated by altered enzyme activity that results from metabolic changes associated with pregnancy. Nevertheless, this study found a high correlation (Pearson chi-square = 13.67, p = .008) between classification of pesticide exposure using self-reported interview information and plasma cholinesterase activity for 203 pregnant women for whom three trimester cholinesterase values were available. All plasma cholinesterase activity values were referenced, by trimester, to a larger sample of 1,050 plasma cholinesterase values from 535 pregnant women. Subjects who lived nearest to agricultural land and who reported that they worked with pesticides in agricultural and other occupations tended to have lower plasma cholinesterase activity than those who reported use of household pesticides only.

  15. Inhibition of cholinesterases by stereoisomers of Huperzine-A

    Energy Technology Data Exchange (ETDEWEB)

    Saxena, A.; Qian, N.; Kovach, I.M.; Ashani, Y.; Kozikowski, A.P.

    1993-05-13

    Huperzine-A, a potential drug for the treatment of Alzheimer's disease and possible pretreament for nerve agent toxicity, has recently been characterized as a reversible inhibitor of cholinesterases (Ashani et al., BBRC, 184:719-726, 1992). Long-term incubation of purified cholinesterases with Huperzine-A did not show any chemical modification of Huperzine-A. The dissociation constant, K(I), for fetal bovine serum acetylcholinesterase (FBS AChE) was approximately 20 nM, for Torpedo AChE was 215 nM, and for horse serum butyrylcholinesterase (BChE) was 40 micrometers M. Inhibition studies with the two stereoisomers of Huperzine-A have shown that naturally occurring (-)-Huperzine-A inhibited FBS AChE 35-fold more potently than (+)-Huperzine-A, with K(I) values of 6.2 nM and 210 nM, respectively. These results are in agreement with those reported previously using crude preparations of rat cortical AChE (McKinney et al., Eur. J. Pharmacol., 203, 303-305, 1991). (-)-Huperzine-A, on the other hand, was 80-fold more potent than (+)-Huperzine-A in inhibiting Torpedo AChE, with K(I), values of 0.25 micrometers M and 22 micrometer M, respectively. No significant differences in K(I) were observed for the two stereoisomers of Huperzine-A with horse serum BChE, indicating the lack of stereoselectivity of this compound for BChE. Molecular modeling studies involving docking of each of the two stereoisomers of Huperzine-A into the active-site gorge of Torpedo AChE also revealed that (-)-Huperzine-A gave a better fit than (+)-Huperzine-A.

  16. Amino Acid Sequence of Human Cholinesterase

    Science.gov (United States)

    1985-10-01

    Michigan Pharmacology Dept., Med. Scd. I Ann Arbor, Michigan 48109-0010 DOD DISTRIBUTION STATEMENT Approved for public release; distribution...ORGANIZATION U’n iversity of Michigan I (f applicable) Pharmacology Dept, Med. Sci. I I.I 6c. ADDRESS (City, State, and ZIP Code) 7b. AODRESS(OZW...digestion with S. aureus protease. For pepsin digestion a cholinesterase preparatlon was used that had not been labeled with DFP and had not been

  17. Cholinesterase characterization in Corbicula fluminea and effects of relevant environmental contaminants: a pesticide (chlorfenvinphos) and a detergent (SDS).

    Science.gov (United States)

    Ramos, Ana S; Gonçalves, Fernando; Antunes, Sara C; Nunes, Bruno

    2012-01-01

    This study characterizes the cholinesterasic forms present in the bivalve Corbicula fluminea, through the analysis of differential affinity towards various substrates and inhibitors. This approach also permitted the validation of cholinesterase inhibition in the mentioned species for monitoring purposes by evaluating the inhibitory activity of a detergent (SDS) and a pesticide (chlorfenvinphos), both in vitro and in vivo. The cholinesterasic form present in the tissues of C. fluminea showed intermediate properties in terms of its relation with substrates and inhibitors. Furthermore, it was not inhibited by the detergent SDS under any of the test conditions, but was clearly inhibited by the selected organophosphate. The data show clearly that the main cholinesterasic form in C. fluminea is responsive to the organophosphate chlorfenvinphos, thus supporting the use of this biomarker for the environmental monitoring of specific contaminants such as anticholinesterasic pesticides. Despite not being commonly attained in the wild, the levels of chlorfenvinphos required to elicit a significant ChE inhibition were only one order of magnitude above actual values of aquatic contamination by this pesticide. Copyright © Taylor & Francis Group, LLC

  18. Time-dependent kinetic complexities in cholinesterase-catalyzed reactions.

    Science.gov (United States)

    Masson, P

    2012-10-01

    Cholinesterases (ChEs) display a hysteretic behavior with certain substrates and inhibitors. Kinetic cooperativity in hysteresis of ChE-catalyzed reactions is characterized by a lag or burst phase in the approach to steady state. With some substrates damped oscillations are shown to superimpose on hysteretic lags. These time dependent peculiarities are observed for both butyrylcholinesterase and acetylcholinesterase from different sources. Hysteresis in ChE-catalyzed reactions can be interpreted in terms of slow transitions between two enzyme conformers E and E'. Substrate can bind to E and/or E', both Michaelian complexes ES and Ε'S can be catalytically competent, or only one of them can make products. The formal reaction pathway depends on both the chemical structure of the substrate and the type of enzyme. In particular, damped oscillations develop when substrate exists in different, slowly interconvertible, conformational, and/or micellar forms, of which only the minor form is capable of binding and reacting with the enzyme. Biphasic pseudo-first-order progressive inhibition of ChEs by certain carbamates and organophosphates also fits with a slow equilibrium between two reactive enzyme forms. Hysteresis can be modulated by medium parameters (pH, chaotropic and kosmotropic salts, organic solvents, temperature, osmotic pressure, and hydrostatic pressure). These studies showed that water structure plays a role in hysteretic behavior of ChEs. Attempts to provide a molecular mechanism for ChE hysteresis from mutagenesis studies or crystallographic studies failed so far. In fact, several lines of evidence suggest that hysteresis is controlled by the conformation of His438, a key residue in the catalytic triad of cholinesterases. Induction time may depend on the probability of His438 to adopt the operative conformation in the catalytic triad. The functional significance of ChE hysteresis is puzzling. However, the accepted view that proteins are in equilibrium between

  19. Phosalone-Induced Changes in Regional Cholinesterase Activities ...

    African Journals Online (AJOL)

    Phosalone-Induced Changes in Regional Cholinesterase Activities in Rat Brain during Behavioral Tolerance. ... PROMOTING ACCESS TO AFRICAN RESEARCH ... The present study was undertaken to examine the activity levels of cholinesterases in different regions of rat brain during the development of behavioral ...

  20. Serum and Plasma Cholinesterase Activity in the Cape Griffon Vulture (Gyps coprotheres).

    Science.gov (United States)

    Naidoo, Vinny; Wolter, Kerri

    2016-04-28

    Vulture (Accipitridae) poisonings are a concern in South Africa, with hundreds of birds dying annually. Although some of these poisonings are accidental, there has been an increase in the number of intentional baiting of poached rhinoceros (Rhinocerotidae) and elephant (Elephantidae) carcasses to kill vultures that alert officials to poaching sites by circling overhead. The primary chemicals implicated are the organophosphorous and carbamate compounds. Although most poisoning events can be identified by dead vultures surrounding the scavenged carcass, weak birds are occasionally found and brought to rehabilitation centers for treatment. The treating veterinarian needs to make an informed decision on the cause of illness or poisoning prior to treatment. We established the reference interval for serum and plasma cholinesterase activity in the Cape Griffon Vulture ( Gyps coprotheres ) as 591.58-1,528.26 U/L, providing a clinical assay for determining potential exposure to cholinesterase-depressing pesticides. Both manual and automated samplers were used with the butyrylthiocholine method. Species reference intervals for both serum and plasma cholinesterase showed good correlation and manual and automated measurements yielded similar results.

  1. Variability in the prescription of cholinesterase inhibitors and memantine

    DEFF Research Database (Denmark)

    Villar-Fernández, I; Bjerrum, L; Feja, C

    2009-01-01

    To estimate the prevalence of Alzheimer's disease (AD) treatment in Aragon (Spain), analyzing differences according to age, gender and health area.......To estimate the prevalence of Alzheimer's disease (AD) treatment in Aragon (Spain), analyzing differences according to age, gender and health area....

  2. Characterizations of cholinesterases in golden apple snail (Pomacea canaliculata).

    Science.gov (United States)

    Zou, Xiang-Hui; Xie, Heidi Qun-Hui; Zha, Guang-Cai; Chen, Vicky Ping; Sun, Yan-Jie; Zheng, Yu-Zhong; Tsim, Karl Wah-Keung; Dong, Tina Ting-Xia; Choi, Roy Chi-Yan; Luk, Wilson Kin-Wai

    2014-07-01

    Cholinesterases (ChEs) have been identified in vertebrates and invertebrates. Inhibition of ChE activity in invertebrates, such as bivalve molluscs, has been used to evaluate the exposure of organophosphates, carbamate pesticides, and heavy metals in the marine system. The golden apple snail (Pomacea canaliculata) is considered as one of the worst invasive alien species harmful to rice and other crops. The ChE(s) in this animal, which has been found recently, but poorly characterized thus far, could serve as biomarker(s) for environmental surveillance as well as a potential target for the pest control. In this study, the tissue distribution, substrate preference, sensitivity to ChE inhibitors, and molecular species of ChEs in P. canaliculata were investigated. It was found that the activities of both AChE and BChE were present in all test tissues. The intestine had the most abundant ChE activities. Both enzymes had fair activities in the head, kidney, and gills. The BChE activity was more sensitive to tetra-isopropylpyrophosphoramide (iso-OMPA) than the AChE. Only one BChE molecular species, 5.8S, was found in the intestine and head, whereas two AChE species, 5.8S and 11.6S, were found there. We propose that intestine ChEs of this snail may be potential biomarkers for manipulating pollutions.

  3. Cholinesterase inhibition reduces arrhythmias in asymptomatic Chagas disease.

    Science.gov (United States)

    Castro, Renata R T; Porphirio, Graciema; Xavier, Sergio S; Moraes, Ruy S; Ferlin, Elton L; Ribeiro, Jorge P; da Nóbrega, Antonio C L

    2017-10-01

    Parasympathetic dysfunction may play a role in the genesis of arrhythmias in Chagas disease. This study evaluates the acute effects of pyridostigmine (PYR), a reversible cholinesterase inhibitor, on the occurrence of arrhythmias in patients with Chagas cardiac disease. Following a double-blind, randomized, placebo-controlled, cross-over protocol, 17 patients (age 50±2 years) with Chagas cardiac disease type B underwent 24-hour Holter recordings after oral administration of either pyridostigmine bromide (45 mg, 3 times/day) or placebo (PLA). Pyridostigmine reduced the 24-hours incidence (median [25%-75%]) of premature ventricular beats-PLA: 2998 (1920-4870), PYR: 2359 (940-3253), P=.044; ventricular couplets-PLA: 84 (15-159), PYR: 33 (6-94), P=.046. Although the total number of nonsustained ventricular tachycardia in the entire group was not different (P=.19) between PLA (1 [0-8]) and PYR (0 [0-4]), there were fewer episodes under PYR in 72% of the patients presenting this type of arrhythmia (P=.033). Acute administration of pyridostigmine reduced the incidence of nonsustained ventricular arrhythmias in patients with Chagas cardiac disease. Further studies that address the use of pyridostigmine by patients with Chagas cardiac disease under a more prolonged follow-up are warranted. © 2017 John Wiley & Sons Ltd.

  4. Annual costs of tumor necrosis factor inhibitors using real-world data in a commercially insured population in the United States.

    Science.gov (United States)

    Schabert, Vernon F; Watson, Crystal; Gandra, Shravanthi R; Goodman, Seth; Fox, Kathleen M; Harrison, David J

    2012-01-01

    To calculate annual cost per treated patient of tumor necrosis factor (TNF) inhibitors etanercept, adalimumab, and infliximab for common approved indications, based on actual TNF-inhibitor use in clinical practice. Adults with ≥1 claim for etanercept, adalimumab, or infliximab between January 2005 and March 2009 were identified from the IMS LifeLink™ Health Plan Claims Database. Patients new to therapy or continuing therapy (i.e., a prior claim for a TNF-inhibitor) were analyzed separately. Included patients had been enrolled from 180 days before the first TNF-inhibitor claim (index date) through 360 days after the index date and had a diagnosis during the pre-index period for rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis. Patients with Crohn's disease, ulcerative colitis, or juvenile idiopathic arthritis were excluded. Annual costs were calculated using wholesale acquisition costs for the TNF-inhibitor and Medicare Physician Fee Schedule for drug administration. Costs from restarting or switching TNF-inhibitor therapy during the first year were included. A total of 27,704 patients (11,528 new, 16,176 continuing) had claims for etanercept, adalimumab, or infliximab, most commonly (65%) for treatment of rheumatoid arthritis. The most commonly used agent was etanercept (14,777 patients; 53%), followed by adalimumab (6862 patients; 25%) and infliximab (6065 patients; 22%). Annual cost per treated patient was etanercept $14,873, adalimumab $17,766, and infliximab $21,256 across all indications. Annual cost per treated patient by disease was (etanercept/adalimumab/infliximab): rheumatoid arthritis ($14,314/$17,700/$20,390), psoriasis ($17,182/$17,682/$23,935), psoriatic arthritis ($15,030/$18,483/$24,974), and ankylosing spondylitis ($14,254/$16,925/$23,056). New and continuing patients showed similar results, with etanercept having the lowest costs. This analysis is limited to three TNF-inhibitors and a US managed-care population

  5. Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity

    Science.gov (United States)

    Sikora, Joanna; Mateusiak, Łukasz; Mikiciuk-Olasik, Elżbieta; Huttunen, Kristiina M.

    2017-01-01

    The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM) may predispose to Alzheimer's disease (AD). The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition) and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition) and BuChE (IC50 = 28 nmol/mL, mixed type inhibition), while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL). Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future. PMID:28770024

  6. Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity

    Directory of Open Access Journals (Sweden)

    Magdalena Markowicz-Piasecka

    2017-01-01

    Full Text Available The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM may predispose to Alzheimer’s disease (AD. The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition and BuChE (IC50 = 28 nmol/mL, mixed type inhibition, while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL. Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.

  7. Gravidade das intoxicações por inseticidas inibidores das colinesterases no noroeste do estado do Paraná, Brasil Gravedad de las intoxicaciones por insecticidas inhibidores de colinesterasa en el noroeste del estado do Paraná, Brasil Severity of the intoxications by cholinesterase inhibitor insecticides registered in the nothwest of the state of Paraná, Brasil

    Directory of Open Access Journals (Sweden)

    Magda Lúcia Félix de Oliveira

    2009-12-01

    clasificadas como severas. La alta incidencia de intoxicación grave y mortalidad sugieren estrategias preventivas referidas a la utilización de estos insecticidas, objetivando restringir el acceso indiscriminado a estos potentes agentes tóxicos.This article has as objective the discussion of the severity of intoxications by cholinesterase inhibitor insecticides, which happened in the Northwest of Paraná, Brasil, starting from an exploratory descriptive study, with retrospective analysis of epidemiological data sheets of the Intoxications Control Center in the University Hospital of Maringá, Paraná, Brasil, referring to patients intoxicated from January, 1994 to December, 2005. 529 cases were analyzed, 168 (31,7% for organophosphates and 167 (31,5% for carbamates. The suicide attempt represented 257 cases (48,5%, the occupational exposure 140 (26,5%, and the accidental 124 (23,5%. Comparing the number of severe intoxications and deaths, it was verified from 100% of deaths to cases severe occupational exposure, 20% for the suicide attempt and 7,5% deaths for the accidental intoxications classified as severe. The high incidence of serious intoxication and mortality suggest preventive strategies in respect of the usage of the insecticides, aiming to restrict the indiscriminate access to these powerful toxic agents.

  8. Study of Serum Amylase and Serum Cholinesterase in Organophosphorus Poisoning

    Directory of Open Access Journals (Sweden)

    Sharan Badiger

    2016-04-01

    Full Text Available Background: Poisoning due to organophosphorus compounds is most commonly seen. Earlier plasma cholinesterase level was used to assess the severity of poisoning. Presently serum amylase is being recommended as a better indicator of severity. Aims and Objectives: To study plasma cholinesterase and serum amylase levels in acute organophosphorus and to correlate serum amylase levels with clinical severity and outcome. Material and Methods: A total of 80 patients in the study admitted to a tertiary care centre within 24 hours with a history of organophosphorus poisoning were included in study. Estimation of plasma cholinesterase and serum rd amylase was done at the time of admission, and on 3 th day and on 5 day. Results: Occurrence of organophosphorus poisoning was more common among age group 21-30 years and among males (57.5%. They were 25 (31.2% farmers, 23 (28.8% st u d e n ts, a n d 2 2 ( 2 7 . 5% h o u s ewi v e s. Monocrotophos (45.0% was commonly used compound. Mean value of plasma cholinesterase and serum amylase at admission are 3693 U/L, and 185.4 U/L. There was significant inhibition of plasma cholinesterase and elevation of serum amylase at th admission with return to normal values on 5 day. Conclusion: Plasma cholinesterase inhibition 200 U/L has been associated with poor prognosis and proneness to respiratory failure.

  9. An improved radiosynthesis of O-(2-[(18) F]fluoroethyl)-O-(p-nitrophenyl)methylphosphonate: A first-in-class cholinesterase PET tracer.

    Science.gov (United States)

    Neumann, Kiel D; Thompson, Charles M; Blecha, Joseph E; Gerdes, John M; VanBrocklin, Henry F

    2017-06-15

    O-(2-Fluoroethyl)-O-(p-nitrophenyl) methylphosphonate 1 is an organophosphate cholinesterase inhibitor that creates a phosphonyl-serine covalent adduct at the enzyme active site blocking cholinesterase activity in vivo. The corresponding radiolabeled O-(2-[(18) F]fluoroethyl)-O-(p-nitrophenyl) methylphosphonate, [(18) F]1, has been previously prepared and found to be an excellent positron emission tomography imaging tracer for assessment of cholinesterases in live brain, peripheral tissues, and blood. However, the previously reported [(18) F]1 tracer synthesis was slow even with microwave acceleration, required high-performance liquid chromatography separation of the tracer from impurities, and gave less optimal radiochemical yields. In this paper, we report a new synthetic approach to circumvent these shortcomings that is reliant on the facile reactivity of bis-(O,O-p-nitrophenyl) methylphosphonate, 2, with 2-fluoroethanol in the presence of DBU. The cold synthesis was successfully translated to provide a more robust radiosynthesis. Using this new strategy, the desired tracer, [(18) F]1, was obtained in a non-decay-corrected radiochemical yield of 8 ± 2% (n = 7) in >99% radiochemical and >95% chemical purity with a specific activity of 3174 ± 345 Ci/mmol (EOS). This new facile radiosynthesis routinely affords highly pure quantities of [(18) F]1, which will further enable tracer development of OP cholinesterase inhibitors and their evaluation in vivo. Copyright © 2017 John Wiley & Sons, Ltd.

  10. [Correlation and interconversion between erythrocyte cholinesterase values obtained by the Michel and the EQM techniques].

    Science.gov (United States)

    Carmona-Fonseca, Jaime

    2006-12-01

    Several techniques are available to measure red cell cholinesterase; therefore, evaluations with several methods provide a measure of concordance. An equation was formulated to transform native data of reference values to reference units of cholinesterase activity as measured by Michel and EQM tests. The experimental design was descriptive, transversal and prospective. The group sampled was a representative adult working population, aged 18-75, without previous exposure to cholinesterase inhibitors pesticides. The individuals were affiliated to the Social Security System and resided in Valle de Aburrá and Cercano Oriente Antioqueño (Antioquia Province, northwestern Colombia). Of 827 individuals, quantitative erythrocytes (Michel y EQM) tests exhibited "r" coefficients between 0.67 and R2 coefficient of 44%.,This indicated that one test explained the results in other test in 44% of the cases. The corelation was higher in Aburrá than in Oriente. The linear model for the 827 individuals was as follows: EQM U/g oxy-hemoglobin = 9.575 U/ g oxy-hemoglobin + 29.791 (Michel delta pH/hour). Michel delta pH/hr = 0.3312 delta pH/hour + 0.0149 (EQM U/g oxy-hemoglobin), where EQM was expressed in U/g oxy-hemoglobin and Michel pH change/hr. Inter-sections (coefficient a) and inclines (coefficient b) were significant in this model. In the adjusted equations, after exclusion of 12 extreme data (1.5% of 827), the r coefficient increased from 0.67 to 0.72 The adjusted equations were as follows: EQM U/g oxy-hemoglobin = 8.1884 U/g oxy-hemoglobin + 31.3920 (Michel delta pH/hour); Michel delta pH/hr = 0.2925 delta pH/hr + 0.0161 (EQM U/g oxy-hemoglobin). This system of linear equations permitted the transformation of Michel (delta PH/ hr) units to EQM (U/g oxy-hemoglobin) units and vice versa. This will facilitate data comparisons by clinicians and epidemiologists who are using these methods of cholinesterase measurement.

  11. Antioxidant and cholinesterase inhibitory activity of a new peptide from Ziziphus jujuba fruits.

    Science.gov (United States)

    Zare-Zardini, Hadi; Tolueinia, Behnaz; Hashemi, Azam; Ebrahimi, Leila; Fesahat, Farzaneh

    2013-11-01

    Antioxidant agents and cholinesterase inhibitors are the foremost drugs for the treatment of Alzheimer's disease (AD). In this study, a new peptide from Ziziphus jujuba fruits was investigated for its inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes as well as antioxidant activity. This peptide was introduced as a new peptide and named Snakin-Z. The Snakin-Z displayed considerable cholinesterase inhibition against AChE and BChE. The half maximal inhibitory concentration (IC50) values of Snakin-Z against AChE and BChE are 0.58 ± 0.08 and 0.72 ± 0.085 mg/mL, respectively. This peptide has 80% enzyme inhibitory activity on AChE and BChE at 1.5 mg/mL. The Snakin-Z also had the high antioxidant activity (IC50 = 0.75 ± 0.09 mg/mL). Thus, it is suggested that Snakin-Z may be beneficial in the treatment of AD. However, more detailed researches are still required as in vivo testing its anticholinesterase and antioxidant activities.

  12. Sesquiterpene Lactones from Cynara cornigera: Acetyl Cholinesterase Inhibition and In Silico Ligand Docking.

    Science.gov (United States)

    Hegazy, Mohamed-Elamir F; Ibrahim, Abeer Y; Mohamed, Tarik A; Shahat, Abdelaaty A; El Halawany, Ali M; Abdel-Azim, Nahla S; Alsaid, Mansour S; Paré, Paul W

    2016-01-01

    Wild artichoke (Cynara cornigera), a thistle-like perennial belonging to the Asteraceae family, is native to the Mediterranean region, northwestern Africa, and the Canary Islands. While the pleasant, albeit bitter, taste of the leaves and flowers is attributed to the sesquiterpene lactones cynaropicrin and cynarin, a comprehensive phytochemical investigation still needs to be reported. In this study seven sesquiterpene lactones were isolated from an aqueous methanol plant extract, including a new halogenated metabolite (1), the naturally isolated compound sibthorpine (2), and five metabolites isolated for the first time from C. cornigera. Structures were established by spectroscopic methods, including HREIMS, (1 )H, (13 )C, DEPT, (1 )H-(1 )H COSY, HMQC, and HMBC-NMR experiments as well as by X-ray analysis. The isolated bioactive nutrients were analyzed for their antioxidant and metal chelating activity. Compound 1 exhibited a potent metal chelating activity as well as a high antioxidant capacity. Moreover, select compounds were effective as acetyl cholinesterase inhibitors presenting the possibility for such compounds to be examined for anti-neurodegenerative activity. A computational pharmacophore elucidation and docking study was performed to estimate the pharmacophoric features and binding conformation of isolated compounds in the acetyl cholinesterase active site. Georg Thieme Verlag KG Stuttgart · New York.

  13. Exposureassessmentof greenhouseworkerswithanti-cholinesterase pesticides by biological monitoring

    Directory of Open Access Journals (Sweden)

    Sh Bakand

    2012-12-01

    Full Text Available   Background and Aims: Organophosphate compounds are the most popular insecticides with the widespread application in pest control. These toxic compounds interfere with the blood cholinesterase and inhibit the cholinestarse activity.Measurement of Cholinesterase activity is widely used for diagnosis of poisoning and adverse effects caused by pesticides. Green-house workers are one of the important occupational groups with the high risk of poisoning with organophosphate and karbamat pesticides .The purpose of this study was to assess the exposure of green-house workers with anti-cholinesterase toxic compounds by measuring the blood cholinesterase activity using electrometric method.   Methods: This research is a descriptive cross sectional study that carried out on farmers of the cucumber green-houses . In this study, 40 workers were selected and their blood cholinesterase enzyme activity were measured using electrometric method . In electrometric method the reduction of cholinesterase activity can be measured through recording the changes of blood pH induced by anticholinestrase agents . The results were analyzed by version16 of spss software.   Results: Based on the obtained results the amount of erythrocyte cholinesterase enzyme inhibition was between 1 / 77% to 35 / 4% and the mean and standard deviation was 23 / 2% ±9 / 68.   Similarly, the amount of plasma cholinesterase enzyme inhibition was between 1% to 28% and the mean and standard deviation was equal to 16/57 ±7 / 92.   Following the analysis of results 25% (n=10 of the workers were identified with no poisoning, 17.5% (n = 7 with minor poisoning , 55% (n=22 with moderate poisoning and 2.5% (n=1 with severe poisoning.     Conclusion : Organophosphate poisoning has been reported as the third cause of poisoning and also the leading cause of poisoning deaths in our country.Therefore, considering the results of this research and the importance of the evaluation of workers exposure

  14. Synthesis and cholinesterase inhibitory activity study of new piperidone grafted spiropyrrolidines.

    Science.gov (United States)

    Basiri, Alireza; Abd Razik, Basma M; Ezzat, Mohammed Oday; Kia, Yalda; Kumar, Raju Suresh; Almansour, Abdulrahman I; Arumugam, Natarajan; Murugaiyah, Vikneswaran

    2017-12-01

    Alzheimer's disease (AD) is a prevalent neurodegenerative disorder, which affected 35 million people in the world. The most practiced approach to improve the life expectancy of AD patients is to increase acetylcholine neurotransmitter level at cholinergic synapses by inhibition of cholinesterase enzymes. A series of unreported piperidone grafted spiropyrrolidines 8(a-p) were synthesized and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Therein, compounds 8h and 8l displayed more potent AChE enzyme inhibition than standard drug with IC50 values of 1.88 and 1.37 µM, respectively. Molecular docking simulations for 8l possessing the most potent AChE inhibitory activities, disclosed its interesting binding templates to the active site channel of AChE enzymes. These compounds are remarkable AChE inhibitors and have potential as AD drugs. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Inhibition of Sheep Liver Cholinesterase Enzyme by the Leaf ...

    African Journals Online (AJOL)

    The efficacies of these crude extract were comparable to that of Huperzine A as a reference standard for cholinesterase inhibition. The anticholinesterase assay serves as an indicator system whose analysis always correspond to the bioluminescent Mycobacterium aurum or tuberculosis expressing firefly luciferase.

  16. 21 CFR 862.3240 - Cholinesterase test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cholinesterase test system. 862.3240 Section 862.3240 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

  17. Neuroactive Multifunctional Tacrine Congeners with Cholinesterase, Anti-Amyloid Aggregation and Neuroprotective Properties

    Directory of Open Access Journals (Sweden)

    Maria Kozurkova

    2011-02-01

    Full Text Available The review summarizes research into the highly relevant topics of cholinesterase and amyloid aggregation inhibitors connected to tacrine congeners, both of which are associated with neurogenerative diseases. Various opinions will be discussed regarding the dual binding site inhibitors which are characterized by increased inhibitor potency against acetylcholin/butyrylcholine esterase and amyloid formation. It is suggested that these compounds can both raise levels of acetylcholine by binding to the active site, and also prevent amyloid aggregation. In connection with this problem, the mono/dual binding of the multifunctional derivatives of tacrine, their mode of action and their neuroprotective activities are reported. The influence of low molecular compounds on protein amyloid aggregation, which might be considered as a potential therapeutic strategy in the treatment of Alzheimer’s disease is also reported. Finally, attention is paid to some physico-chemical factors, such as desolvation energies describing the transfer of the substrate solvated by water, the metal-chelating properties of biometals reacting with amyloid precursor protein, amyloid beta peptide and tau protein.

  18. Amyloid, cholinesterase, melatonin, and metals and their roles in aging and neurodegenerative diseases.

    Science.gov (United States)

    Lahiri, Debomoy K; Chen, De-Mao; Lahiri, Preeti; Bondy, Steve; Greig, Nigel H

    2005-11-01

    The aging brain shows selective neurochemical changes involving several neural cell populations. Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Melatonin levels are decreased in aging, particularly in AD subjects. The loss of melatonin, which is synthesized by the pineal gland, together with the degeneration of cholinergic neurons of the basal forebrain and the deposition of aggregated proteins, such as the amyloid beta peptides (Abeta), are believed to contribute to the development of cognitive symptoms of dementia. Aging and its variants, such as AD, should be viewed as the result of multiple "hits," including alterations in the levels of Abeta, metals, cholinesterase enzymes, and neuronal gene expression. Herein, we present evidence in support of this theory, based on several studies. We discuss melatonin's neuroprotective function, which plays an important role in aging, prolongation of life span, and health in the aged individual. It interacts with metals and, in some cases, neutralizes their toxic effects. Dietary supplementation of melatonin restores its age-related loss. In mice, an elevated brain melatonin significantly reduced levels of potentially toxic Abeta peptides. Thus, compensation of melatonin loss in aging by dietary supplementation could well be beneficial in terms of reducing metal-induced toxicity, lipid peroxidation, and losses in cholinergic signaling. We propose that certain cholinesterase inhibitors and the NMDA partial antagonist memantine, which are FDA-approved drugs for AD and useful to boost central nervous system functioning, can be made more effective by their combination with melatonin or other neuroprotectants. Herein, we highlight studies elucidating the role of the amyloid pathway, metals, melatonin, and the cholinergic system in the context of aging and AD. Finally, melatonin is present in edible plants and walnuts, and consuming foodstuffs

  19. Evaluation of Antioxidant, Anti-cholinesterase, and Anti-inflammatory Effects of Culinary MushroomPleurotus pulmonarius.

    Science.gov (United States)

    Nguyen, Trung Kien; Im, Kyung Hoan; Choi, Jaehyuk; Shin, Pyung Gyun; Lee, Tae Soo

    2016-12-01

    Culinary mushroom Pleurotus pulmonarius has been popular in Asian countries. In this study, the anti-oxidant, cholinesterase, and inflammation inhibitory activities of methanol extract (ME) of fruiting bodies of P. pulmonarius were evaluted. The 1,1-diphenyl-2-picryl-hydrazy free radical scavenging activity of ME at 2.0 mg/mL was comparable to that of butylated hydroxytoluene, the standard reference. The ME exhibited significantly higher hydroxyl radical scavenging activity than butylated hydroxytoluene. ME showed slightly lower but moderate inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase than galantamine, a standard AChE inhibitor. It also exhibited protective effect against cytotoxicity to PC-12 cells induced by glutamate (10~100 µg/mL), inhibitory effect on nitric oxide (NO) production and inducible nitric oxide synthase protein expression in lipopolysaccharide-stimulated RAW 264.7 macrophages, and carrageenan-induced paw edema in a rat model. High-performance liquid chromatography analysis revealed the ME of P. pulmonarius contained at least 10 phenolic compounds and some of them were identified by the comparison with known standard phenolics. Taken together, our results demonstrate that fruiting bodies of P. pulmonarius possess antioxidant, anti-cholinesterase, and inflammation inhibitory activities.

  20. HPTLC Fingerprinting and Cholinesterase Inhibitory and Metal-Chelating Capacity of Various Citrus Cultivars and Olea europaea

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    Fatma Sezer Senol

    2016-01-01

    Full Text Available Inhibitory activity of thirty-one ethanol extracts obtained from albedo, flavedo, seed and leaf parts of 17 cultivars of Citrus species from Turkey, the bark and leaves of Olea europaea L. from two locations (Turkey and Cyprus as well as caff eic acid and hesperidin was tested against acetylcholinesterase (AChE and butyrylcholinesterase (BChE, related to the pathogenesis of Alzheimer’s disease, using ELISA microtiter assays at 500 μg/mL. Metal-chelating capacity of the extracts was also determined. BChE inhibitory effect of the Citrus sp. extracts was from (7.7±0.7 to (70.3±1.1 %, whereas they did not show any inhibition against AChE. Cholinesterase inhibitory activity of the leaf and bark ethanol extracts of O. europaea was very weak ((10.2±3.1 to (15.0±2.3 %. The extracts had either no or low metal-chelating capacity at 500 μg/mL. HPTLC fingerprinting of the extracts, which indicated a similar phytochemical pattern, was also done using the standards of caffeic acid and hesperidin with weak cholinesterase inhibition. Among the screened extracts, the albedo extract of C. limon ‘Interdonato’, the flavedo extracts of ‘Kara Limon’ and ‘Cyprus’ cultivars and the seed extract of C. maxima appear to be promising as natural BChE inhibitors.

  1. Studies on the molecular dissection of human cholinesterase variants and their genomic origins. Final report, 1 June 1994-30 May 1996

    Energy Technology Data Exchange (ETDEWEB)

    Soreq, H.

    1996-06-01

    To evaluate the capacity of overexpressed recombinant human cholinesterases or mutated variants thereof to confer protection against anti-cholinesterase toxicity, we employed transiently transgenic Xenopus laevis tadpoles and stably transgenic mice. Normal and mutant variants of butyrylcholinesterase (BuChE) revealed partially overlapping binding sites for several inhibitors and demonstrated the involvement of the oxyanion hole in BuChE catalysis. In the developing tadpoles the isoform of AChE, which terminates with the 3`-exon 6, was efficiently accumulated in neuromuscular junctions and conferred resistance to the organophosphate paraoxon. In transgenic mice, exon 6-terminated AChE, under control of its authentic promoter, accumulated in CNS synapses and conferred resistance to paraoxon and several cholinergic agonists, but caused progressive deterioration in both neuromotor and cognitive functioning. Finally, in a human patient carrying the atypical`1 (D7OG) gene for BuChE, we observed adverse responses to prophylactic doses of the carbamate pyridostigmine and from this and in vitro studies predicted a generalized genetic predisposition to anti-cholinesterase therapies, including that approved for the treatment of Alzheimer`s disease.

  2. Plasma cholinesterase activity of rats, western grey kangaroos, alpacas, sheep, cattle, and horses.

    Science.gov (United States)

    Mayberry, Chris; Mawson, Peter; Maloney, Shane K

    2015-01-01

    Plasma cholinesterase activity levels of various species may be of interest to toxicologists or pathologists working with chemicals that interfere with the activity of plasma cholinesterase. We used a pH titration method to measure the plasma cholinesterase activity of six mammalian species. Plasma cholinesterase activity varied up to 50-fold between species: sheep (88 ± 45 nM acetylcholine degraded per ml of test plasma per minute), cattle (94 ± 35), western grey kangaroos (126 ± 92), alpaca (364 ± 70), rats (390 ± 118) and horses (4539 ± 721). We present a simple, effective technique for the assay of plasma cholinesterase activity levels from a range of species. Although labour-intensive, it requires only basic laboratory equipment. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Automated conductimetric assay of human serum cholinesterase activity.

    Science.gov (United States)

    Duffy, P; Wallach, J M

    1989-01-01

    Serum cholinesterase activity was determined by conductimetry using samples in the microliter range. Butyrylcholine iodide was demonstrated to be a convenient substrate for the conductimetric assay. Validation of the microassay was made by using either purified enzyme or control serum. In the range of 0-60 U/l, a linear relationship was demonstrated. Correlation with a reference spectrophotometric method was obtained with a slope of 1.18. An explanation of this value is proposed, as different hydrolysis rates were obtained with human sera, depending on the substrate used (butyrylthio- or butyryl-choline ester).

  4. Acetylcholine-hydrolyzing activities in soluble brain fraction: Characterization with reversible and irreversible inhibitors.

    Science.gov (United States)

    Estévez, Jorge; Selva, Verónica; Benabent, Mónica; Mangas, Iris; Sogorb, Miguel Ángel; Vilanova, Eugenio

    2016-11-25

    Some effects of organophosphorus compounds (OPs) esters cannot be explained through actions on currently recognized targets acetylcholinesterase or neuropathy target esterase (NTE). In soluble chicken brain fraction, three components (Eα, Eβ and Eγ) of pheny lvalerate esterase activity (PVase) were kinetically discriminated and their relationship with acetylcholine-hydrolyzing activity (cholinesterase activity) were studied in previous works. In this work, four enzymatic components (CS1, CS2, CS3 and CS4) of cholinesterase activity have been discriminated in soluble fraction, according to their sensitivity to irreversible inhibitors mipafox, paraoxon, PMSF and iso-OMPA and to reversible inhibitors ethopropazine and BW284C51. Cholinesterase component CS1 can be related to the Eα component of PVase activity and identified as butyrylcholinesterase (BuChE). No association and similarities can be stablished among the other PVase component (Eβ and Eγ) with the other cholinesterase components (CS2, CS3, CS4). The kinetic analysis has allowed us to stablish a method for discriminating the enzymatic component based on a simple test with two inhibitors. It can be used as biomarker in toxicological studies and for monitoring these cholinesterase components during isolation and molecular identification processes, which will allow OP toxicity to be understood by a multi-target approach. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Coumarin derivatives bearing benzoheterocycle moiety: synthesis, cholinesterase inhibitory, and docking simulation study

    Directory of Open Access Journals (Sweden)

    Kimia Hirbod

    2017-06-01

    Full Text Available Objective(s: To investigate the efficiency of a novel series of coumarin derivatives bearing benzoheterocycle moiety as novel cholinesterase inhibitors. Materials and Methods: Different 7-hydroxycoumarin derivatives were synthesized via Pechmann or Knoevenagel condensation and conjugated to different benzoheterocycle (8-hydroxyquinoline, 2-mercaptobenzoxazole or 2-mercaptobenzimidazole using dibromoalkanes 3a-m. Final compounds were evaluated against acetylcholinesterase (AChE and butyrylcholinesterase (BuChE by Ellman's method. Kinetic study of AChE inhibition and ligand-protein docking simulation were also carried out for the most potent compound 3b. Results: Some of the compounds revealed potent and selective activity against AChE. Compound 3b containing the quinoline group showed the best activity with an IC50 value of 8.80 µM against AChE. Kinetic study of AChE inhibition revealed the mixed-type inhibition of the enzyme by compound 3b. Ligand-protein docking simulation also showed that the flexibility of the hydrophobic five carbons linker allows the quinoline ring to form π-π interaction with Trp279 in the PAS. Conclusion: We suggest these synthesized compounds could become potential leads for AChE inhibition and prevention of AD symptoms.

  6. Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse.

    Science.gov (United States)

    Steinebrunner, Niels; Mogler, Carolin; Vittas, Spiros; Hoyler, Birgit; Sandig, Catharina; Stremmel, Wolfgang; Eisenbach, Christoph

    2014-08-19

    Acetaminophen (APAP) is one of the most widely used analgesic and antipyretic pharmaceutical substances in the world and accounts for most cases of drug induced liver injury resulting in acute liver failure. Acute liver failure initiates a sterile inflammatory response with release of cytokines and innate immune cell infiltration in the liver. This study investigates, whether pharmacologic acetylcholinesterase inhibition with neostigmine diminishes liver damage in acute liver failure via the cholinergic anti-inflammatory pathway. Acute liver failure was induced in BALB/c mice by a toxic dose of acetaminophen (APAP). Neostigmine and/or N-acetyl-cysteine (NAC) were applied therapeutically at set time points and the survival was investigated. Liver damage was assessed by serum parameters, histopathology and serum cytokine assays 12 h after initiation of acute liver failure. Serum parameters, histopathology and serum cytokine assays showed pronounced features of acute liver failure 12 h after application of acetaminophen (APAP). Neostigmine treatment led to significant reduction of serum liver enzymes (LDH (47,147 ± 12,726 IU/l vs. 15,822 ± 10,629 IU/l, p = 0.0014) and ALT (18,048 ± 4,287 IU/l vs. 7,585 ± 5,336 IU/l, p = 0.0013), APAP-alone-treated mice vs. APAP + neostigmine-treated mice), inflammatory cytokine levels (IL-1β (147 ± 19 vs. 110 ± 25, p = 0.0138) and TNF-α (184 ± 23 vs. 130 ± 33, p = 0.0086), APAP-alone-treated mice vs. APAP + neostigmine-treated mice) and histopathological signs of damage.Animals treated with NAC in combination with the peripheral cholinesterase inhibitor neostigmine showed prolonged survival and improved outcome. Neostigmine is an acetylcholinesterase inhibitor that ameliorates the effects of APAP-induced acute liver failure in the mouse and therefore may provide new treatment options for affected patients.

  7. Evaluation of flow injection analysis for determination of cholinesterase activities in biological material.

    Science.gov (United States)

    Cabal, Jiri; Bajgar, Jiri; Kassa, Jiri

    2010-09-06

    The method for automatic continual monitoring of acetylcholinesterase (AChE) activity in biological material is described. It is based on flexible system of plastic pipes mixing samples of biological material with reagents for enzyme determination; reaction product penetrates through the semipermeable membrane and it is spectrophotometrically determined (Ellman's method). It consists of sampling (either in vitro or in vivo), adding the substrate and flowing to dialyzer; reaction product (thiocholine) is dialyzed and mixed with 5,5'-dithio-bis-2-nitrobenzoic acid (DTNB) transported to flow spectrophotometer. Flowing of all materials is realised using peristaltic pump. The method was validated: time for optimal hydratation of the cellophane membrane; type of the membrane; type of dialyzer; conditions for optimal permeation of reaction components; optimization of substrate and DTNB concentrations (linear dependence); efficacy of peristaltic pump; calibration of analytes after permeation through the membrane; excluding of the blood permeation through the membrane. Some examples of the evaluation of the effects of AChE inhibitors are described. It was demonstrated very good uniformity of peaks representing the enzyme activity (good reproducibility); time dependence of AChE inhibition caused by VX in vitro in the rat blood allowing to determine the half life of inhibition and thus, bimolecular rate constants of inhibition; reactivation of inhibited AChE by some reactivators, and continual monitoring of the activity in the whole blood in vivo in intact and VX-intoxicated rats. The method is simple and not expensive, allowing automatic determination of AChE activity in discrete or continual samples in vitro or in vivo. It will be evaluated for further research of cholinesterase inhibitors. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  8. Inhibition of cholinesterase by essential oil from food plant.

    Science.gov (United States)

    Chaiyana, Wantida; Okonogi, Siriporn

    2012-06-15

    Inhibition of cholinesterase has attracted much attention recently because of its potential for the treatment of Alzheimer's disease. In this work, the anticholinesterase activities of plant oils were investigated using Ellman's colorimetric method. The results indicate that essential oils obtained from Melissa officinalis leaf and Citrus aurantifolia leaf showed high acetylcholinesterase and butyrylcholinesterase co-inhibitory activities. C. aurantifolia leaf oil revealed in this study has an IC(50) value on acetylcholinesterase and butyrylcholinesterase of 139 ± 35 and 42 ± 5 μg/ml, respectively. GC/MS analysis revealed that the major constituents of C. aurantifolia leaf oil are monoterpenoids including limonene, l-camphor, citronellol, o-cymene and 1,8-cineole. Copyright © 2012 Elsevier GmbH. All rights reserved.

  9. [Study of the interaction of main potato glycoalkaloids in inhibition of immobilized butyryl cholinesterase].

    Science.gov (United States)

    Arkhypova, V M; Dziadevych, S V; Jaffrezic-Renault, N; Martelet, C; Soldatkin, O P

    2006-01-01

    The interaction of main potato glycoalkaloids alpha-solanine and alpha-chaconine in inhibition of horse serum butyryl cholinesterases immobilized on the pH-sensitive field-effect transistors has been investigated. The method of isobol diagram of Loewe and Muishnek has been used for interpretation of results. It has been shown the alpha-chaconine inhibits the immobilized bytyryl cholinesterases more strongly than alpha-solanine, and their mixture has the addition effect.

  10. Electrometric measurement of plasma, erythrocyte, and whole blood cholinesterase activities in healthy human volunteers.

    Science.gov (United States)

    Mohammad, F K; Alias, A S; Ahmed, O A H

    2007-03-01

    The measurement of blood cholinesterase activity is a useful tool for monitoring exposure to organophosphate and carbamate insecticides. Blood cholinesterase activity is measured colorimetrically or electrometrically. Recently, a simple and practical electrometric method has been described and validated for measuring blood cholinesterase activity in people and animals. The purpose of the present report was to use the modified electrometric technique for measuring blood (plasma, erythrocyte and whole blood) cholinesterase activities in apparently healthy human volunteers in Mosul, Iraq. Cholinesterase activities in the plasma, erythrocytes, and whole blood of healthy male (n = 72) and female (n = 31) volunteers were measured by an electrometric method; the method involved the addition of 0.2 ml of blood sample to 3 ml of distilled water followed by 3 ml of barbital-phosphate buffer solution (pH 8.1). The pH (pH1) of the mixture was measured, and then 0.1 ml of 7.5% of acetylcholine iodide, as a substrate, was added. The reaction mixture was incubated at 37 degrees C for 20 minutes. The pH (pH2) of the reaction mixture was measured after the end of the incubation period. Enzyme activity was expressed as DeltapH/20 min = pH1- pH2 - (DeltapH of the blank). The blank was without the blood sample. Following in vitro inhibition of pseudo cholinesterase by quinidine sulfate, true cholinesterase activity was estimated in the plasma of the subjects. After in vitro addition of the organophosphate (chlorpyrifos and methidathion, 0.5 and 1 microM) and carbamate (carbaryl, 5 and 10 microM) insecticides to the reaction mixtures, inhibitions of blood cholinesterases were measured. Mean reference cholinesterase activities (DeltapH/20 min) in the plasma, erythrocytes, and whole blood of male subjects were 0.98, 1.39, and 1.41, respectively. Females were 0.85, 1.22, and 1.23, respectively. Ten minutes after in vitro addition of quinidine sulfate to inhibit pseudo cholinesterase

  11. Evaluating reptile exposure to cholinesterase-inhibiting agrochemicals by serum butyrylcholinesterase activity.

    Science.gov (United States)

    Sanchez-Hernandez, Juan C

    2003-02-01

    Blood samples from lizards (Gallotia galloti) collected from two agricultural areas (Las Galletas and Punta del Hidalgo) and two reference areas on the Island of Tenerife (Canary Islands, Spain) were analyzed for butyrylcholinesterase (BChE) activity. Serum BChE activity was characterized first by in vitro experiments using selective substrates and inhibitors. Of the total cholinesterase (ChE) activity, 74% could be attributed to BChE activity. This portion of the total ChE activity was inhibited dose dependently by tetraisopropyl pyrophosphoramide and hydrolyzed the substrate butyrylthiocholine iodide. No enzyme inhibition was observed at high substrate concentration. Twenty-one lizards collected from agricultural sampling sites showed significant inhibition (p Galletas and 5.13 +/- 1.48 for lizards from Punta del Hidalgo) compared with BChE activity for lizards from the reference sites (6.35 +/- 1.75 micromol/min/ ml). Las Galletas had the highest number of lizards (22%) with significantly inhibited BChE activity. In vitro assays showed that 10(-4) M pyridine-2-aldoxime methochloride (2-PAM) reactivated dichlorvos- or paraoxon-inhibited BChE activity within a 60-min incubation period. Almost all serum samples with depressed BChE activity that were collected from lizards from agricultural areas responded to 2-PAM reactivation of enzyme activity (8-60% increase in enzyme activity). Reactivation by treatment with 2-PAM confirmed that the depression of BChE activity was attributable to organophosphorus (OP) compounds. Evaluation of BChE activity levels and the chemical reactivation of serum BChE activity in G. galloti using 2-PAM was found to be a sensitive indicator of G. galloti exposure to OP compounds.

  12. Partial protection from organophosphate-induced cholinesterase inhibition by metyrapone treatment

    Directory of Open Access Journals (Sweden)

    Radosław Świercz

    2013-08-01

    Full Text Available Background: Organophosphates are cholinesterase (ChE inhibitors with worldwide use as insecticides. Stress response, evidenced by a dramatic and relatively long-lasting (several hours rise in the plasma glucocorticoid concentration is an integral element of the organophosphate (OP poisoning symptomatology. In rodents, corticosterone (CORT is the main glucocorticoid. There are several reports suggesting a relationship between the stressor-induced rise in CORT concentraion (the CORT response and the activity of the cerebral and peripheral ChE. Thus, it seems reasonable to presume that, in OP intoxication, the rise in plasma CORT concentration may somehow affect the magnitude of the OP-induced ChE inhibition. Metyrapone (MET [2-methyl-1,2-di(pyridin-3-ylpropan-1-one] blocks CORT synthesis by inhibiting steoid 11β-hydroxylase, thereby preventing the CORT response. Chlorfenvinphos (CVP [2-chloro-1-(2,4-dichlorophenyl ethenyl diethyl phosphate] is an organophosphate insecticide still in use in some countries. Material and Methods: The purose of the present work was to compare the CVP-induced effects - the rise of the plasma CORT concentration and the reduction in ChE activity - in MET-treated and MET-untreated rats. Chlorfenvinphos was administered once at 0.0, 0.5, 1.0 and 3.0 mg/kg i.p. Metyrapone, at 100 mg/kg i.p., was administered five times, at 24-h intervals. The first MET dose was given two hours before CVP. Conclusion: The following was observed in the MET-treated rats: i no rise in plasma CORT concentration after the CVP administration, ii a reduced inhibition and a faster restitution of blood and brain ChE activities. The results suggest that MET treatment may confer significant protection against at least some effects of OP poisoning. The likely mechanism of the protective MET action has been discussed.

  13. Partial protection from organophosphate-induced cholinesterase inhibition by metyrapone treatment.

    Science.gov (United States)

    Swiercz, Radosław; Lutz, Piotr; Gralewicz, Sławomir; Grzelińska, Zofia; Piasecka-Zelga, Joanna; Wąsowicz, Wojciech

    2013-08-01

    Organophosphates are cholinesterase (ChE) inhibitors with worldwide use as insecticides. Stress response, evidenced by a dramatic and relatively long-lasting (several hours) rise in the plasma glucocorticoid concentration is an integral element of the organophosphate (OP) poisoning symptomatology. In rodents, corticosterone (CORT) is the main glucocorticoid. There are several reports suggesting a relationship between the stressor-induced rise in CORT concentration (the CORT response) and the activity of the cerebral and peripheral ChE. Thus, it seems reasonable to presume that, in OP intoxication, the rise in plasma CORT concentration may somehow affect the magnitude of the OP-induced ChE inhibition. Metyrapone (MET) [2-methyl-1,2-di(pyridin-3-yl)propan-1-one] blocks CORT synthesis by inhibiting steroid 11β-hydroxylase, thereby preventing the CORT response. Chlorfenvinphos (CVP) [2-chloro-1-(2,4-dichlorophenyl) ethenyl diethyl phosphate] is an organophosphate insecticide still in use in some countries. The purpose of the present work was to compare the CVP-induced effects - the rise of the plasma CORT concentration and the reduction in ChE activity - in MET-treated and MET-untreated rats. Chlorfenvinphos was administered once at 0.0, 0.5, 1.0 and 3.0 mg/kg i.p. Metyrapone, at 100 mg/kg i.p., was administered five times, at 24-h intervals. The first MET dose was given two hours before CVP. The following was observed in the MET-treated rats: i) no rise in plasma CORT concentration after the CVP administration, ii) a reduced inhibition and a faster restitution of blood and brain ChE activities. The results suggest that MET treatment may confer significant protection against at least some effects of OP poisoning. The likely mechanism of the protective MET action has been discussed.

  14. Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

    Directory of Open Access Journals (Sweden)

    Miroslav Pohanka

    2014-06-01

    Full Text Available Acetylcholinesterase (AChE inhibitors are widely used for the symptomatic treatment of Alzheimer’s disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE. Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a “cholinergic anti-inflammatory pathway” which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system.

  15. Distribution pattern of cholinesterase enzymes in human tooth germs.

    Science.gov (United States)

    Nandasena, T L; Jayawardena, C K; Tilakaratne, W M; Nanayakkara, C D

    2010-08-01

    The two distinct molecular forms of cholinesterase (ChE) are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Our previous studies have reported that ChE is involved in tooth development. However, further experiments are needed to understand the precise action of ChE in tooth development. This study aimed to localise types of ChE in human tooth germs, and identify their distribution pattern. ChE were localised in frozen sections of jaws which were prepared from dead fetuses, neonates and stillborns who were free from visible abnormalities by Karnovsky and Root method. AChE was identified in the inner and outer enamel epithelia including the cervical loop region, stratum intermedium and preameloblasts of tooth germs at bell stage. Secretory ameloblasts were free from staining. The bud and cap stages of permanent tooth germs showed AChE activity on the lingual aspect and top surface of the epithelial ingrowths, respectively. BuChE activity was localised in the degenerating dental lamina. Our study reported the first evidence of localisation of ChE in human tooth development and identified the possible molecular form of ChE in tooth germs as AChE. Also, our results have provided strong evidence to speculate the action of AChE is on the cells of enamel organ during tooth development.

  16. Cholinesterases activities and lipid peroxidation levels in muscle from shelf and slope dwelling fish from the NW Mediterranean: its potential use in pollution monitoring.

    Science.gov (United States)

    Solé, M; Lobera, G; Aljinovic, B; Ríos, J; García de la Parra, L M; Maynou, F; Cartes, J E

    2008-09-01

    We selected muscle tissue from nine commercial fish species, seven teleosts and two elasmobranchs, frequently caught in the NW Mediterranean trawling grounds in two different habitats (the continental shelf at 53 m and the slope at 660 m) for cholinesterases (ChEs) characterisation and activities determination, as well as the measure of lipid peroxidation (LP) levels. Acethyl- (AChE), butyryl- (BChE) and propionyl- (PrChE) cholinesterase were chosen as exposure markers of neurotoxic chemicals/molecules and LP as an effect marker of oxidative damage. The use of diagnose inhibitors: eserine sulphate, iso-OMPA and BW284c51 confirmed the measurement of true ChEs as well as the presence of pseudocholinesterases. The present study has evidenced the existence of interspecies differences, especially between teleosts and elasmobranchs but not in relation to depth. Moreover, the good correlation observed between all ChEs in most of the studied fish, supports the use of AChE as neurotoxic marker in field pollution monitoring. The non-metric multidimensional scaling analysis identified the commercial species hake Merluccius merluccius, among teleosts, and the shark, Galeus melastomus, as more adequate sentinel species in commercial fishing grounds. AChE activity showed a relationship with the fish trophic level, while all ChEs revealed a relationship with the feeding habits (benthic, suprabenthic, pelagic) and the stomach fullness. BChE activity and LP levels were the only markers to show a relationship with their swimming capacity.

  17. Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil

    CSIR Research Space (South Africa)

    Van Greunen, DG

    2017-02-01

    Full Text Available an in vitro IC(sub50) value of 0.03 ± 0.07 µM against acetylcholinesterase with no cytotoxicity observed (IC(sub50) of >100 µM, SH-SY5Y cell line). In comparison donepezil had an IC(sub50) of 0.05 ± 0.06 µM and an observed cytotoxicity IC(sub50) of 15.54 ± 1...

  18. Behavioral Effects of Low Doses of Cholinesterase Inhibitors in Robot- Tested Marmosets

    Science.gov (United States)

    1989-10-01

    and in contrapt to rodents. Third, in vivo and in vitro studies showed that the marmoset responded to oxime therapy differently from mice, rats, guinea...28 CARBAMATES ON PERFORMANCE DISCRIM. PERF. : ATTEMPTS ( SERES 21 saW e aiysost e 0.02 nq MhysoeCktnWWe 0.04 mqk I Ito IIs. 0" "" 𔃽 15? carbamates as in figure 5. * . -**j ."-

  19. Two new cholinesterase inhibitors asiatoates A and B from Buddleja asiatica.

    Science.gov (United States)

    Ali, Farman; Khan, Hidayat Ullah; Afzal, Masood; Samad, Abdul; Khan, Shafi Ullah; Ali, Irshad

    2013-01-01

    Two new benzoates, asiatoate A (1) and asiatoate B (2), have been isolated from the ethyl acetate soluble fraction of Buddleja asiatica whole plant. Their structures were elucidated with the help of spectroscopic data. Both showed significant inhibitory effect on acetylcholinesterase (AChE) and butylcholinesterase (BChE) in a dose-dependent manner. The IC50 values of compounds 1-2 were 5.54 and 8.34 μM against AChE while 30.94 and 35.94 μM against BChE, respectively.

  20. Individualized evaluation of cholinesterase inhibitors effects in dementia with adaptive cognitive testing

    NARCIS (Netherlands)

    Wouters, Hans; Van Campen, Jos P C M; Appels, Bregje A; Beijnen, Jos H; Zwinderman, Aeilko H; Van Gool, Willem A; Schmand, Ben

    2015-01-01

    Computerized Adaptive Testing (CAT) of cognitive function, selects for every individual patient, only items of appropriate difficulty to estimate his or her level of cognitive impairment. Therefore, CAT has the potential to combine brevity with precision. We retrospectively examined the evaluation

  1. Cholinesterase inhibitors are compatible with psychosocial intervention for Alzheimer disease patients suggested by neuroimaging findings.

    Science.gov (United States)

    Meguro, Kenichi

    2017-01-30

    We previously reported that the frontal lobe was stimulated by psychosocial intervention for dementia patients, and that the parietal lobe was associated with logical judgment. We hypothesized that the combined therapeutic approach with symptomatic drug treatment can directly stimulate not only attention function but also judgment function indirectly to observing other participants' behaviors. Fifty-two patients with Alzheimer disease underwent the group reminiscence approach with reality orientation, as well as the donepezil treatment. The cerebral blood flow (CBF) was assessed with 99m Tc-ECD SPECT. Two analyses were performed: Analysis 1 was to compare Responders vs. Non-responders as shown by MMSE scores, whereas Analysis 2 was to compare Good vs. Poor reminders of the intervention content. We found that the CBF in the frontal lobe was significantly higher in Responders (vs. Non-responders). The CBF in the parietal lobe, especially the left side, was significantly higher in the Good reminders (vs. Poor reminders). The donepezil stimulated the areas similar to where the psychosocial intervention was previously found to be stimulated directly, thus the drug was thought to be compatible for psychosocial intervention. The parietal lobe was stimulated indirectly, suggesting that the indirect effect of the intervention may be based on logical judgment function. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. [Morpho-functional changes in the liver after exposure to cholinesterase inhibitors].

    Science.gov (United States)

    Kravtsova, G B

    1983-07-01

    A single administration of chlorophos (trichlorophon) solution (600 mg/kg) (LD50) results in vacuolar distrophy appearing in the white rat liver and is especially pronounced in 2-4 days. Thirty minutes after the poisonous chemical is administered, butyrilcholinesterase (BChE) activity is inhibited by 90%, somewhat later oxidation-reduction enzymes activity decreases and alkaline phosphatase (APh) activity increases. Cytoplasm of hepatocytes is filled with glycogene and nearly deprived of RNA. Owing to the cytophotometric analysis of the enzymatic activity and the stereologic morphometry method, it has been possible to reveal a certain synchronism in the development of distrophic processes, in a decreasing activity of the oxidation-reduction enzymes and in a disturbed synthesis of glycogene and RNA. On the 6th day after chlorophos has been administered, succinate dehydrogenase and nicotinamide-adenine-dinucleotide-phosphate-diaphorase activity, as well as contents and distribution of RNA in hepatocytes reach their control values. BChE and APh activity does not restore. During the whole experiment there is not any statistically significant change in the volumetric part of the sinusoid capillaries and in the stellate reticuloendotheliocytes. Thus, the main effect of chlorophos action is a specific inhibition of ChE, that results in certain structural changes and in changes of the histoenzymatic parameters of the liver.

  3. Cholinesterase assay by an efficient fixed time endpoint method

    Directory of Open Access Journals (Sweden)

    Mónica Benabent

    2014-01-01

    The method may be adapted to the user needs by modifying the enzyme concentration and applied for simultaneously testing many samples in parallel; i.e. for complex experiments of kinetics assays with organophosphate inhibitors in different tissues.

  4. AChE inhibitor: a regio- and stereo-selective 1,3-dipolar cycloaddition for the synthesis of novel substituted 5,6-dimethoxy spiro[5.3']-oxindole-spiro-[6.3″]-2,3-dihydro-1H-inden-1″-one-7-(substituted aryl)-tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole.

    Science.gov (United States)

    Ashraf Ali, Mohamed; Ismail, Rusli; Choon, Tan Soo; Kumar, Raju Suresh; Osman, Hasnah; Arumugam, Natarajan; Almansour, Abdulrahman I; Elumalai, Karthikeyan; Singh, Abhimanyu

    2012-01-01

    Pyrrolothiazolyloxindole analogues share vital pharmacological properties, considered useful in Alzheimer's disease (AD). The aim of this study was synthesis and evaluate pyralothiazolyloxindole analogues if possess acetyl cholinesterase (AChE) inhibitory activity. The easily accessible one-pot synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compound was the most potent inhibitors of the series against acetyl cholinesterase enzyme with IC(50) 0.11μmol/L. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. RBC acetyl cholinesterase: A poor man′s early diagnostic biomarker for familial alzheimer′s and Parkinson′s disease dementia

    Directory of Open Access Journals (Sweden)

    Himmatrao Saluba Bawaskar

    2015-01-01

    Full Text Available Objective: Analysis of red blood cell acetyl cholinesterase (AChE in a familial Alzheimer′s diseases (AD Parkinson′s disease dementia (PDD and their first generation. Setting: General hospital, Mahad district, Raigad. Patients and Methods: Clinically diagnosed patients of AD and PDD and their asymptomatic relatives. Their blood was collected in EDTA tube and transferred to laboratory at Mumbai. Result: Median red blood cell (RBC cholinesterase levels amongst PDD, their first generation asymptomatic relatives, familial AD, asymptomatic relatives of AD, healthy controls, farmers exposed to pesticides (positive control and other neurological condition without dementia (hypertension with TIA 1, sub-dural hematoma 2, hypothyroid 1, non-familial unilateral parkinsonism without dementia 3, writers cramps 2, hyponitremia 1 and cerebral palsy with non-fluent aphasia 1. Median values of RBC AChE were 19086.78 U/L, 15666.05 U/L, 9013.11 U/L, 7806.19 U/L, 14334.57 U/L, 9785.05 U/L and 13162.60 U/L, respectively. As compared to controls, RBC AChE levels were statistically significant among PDD (P = 0.004 and significantly lowered among familial AD patients (P = 0.010, relatives of patients (P = 0.010. Interpretations: Below the normal RBC AChE level is a potential biomarker in asymptomatic relatives of familial AD patients. RBC AChE is raised than normal level in patients suffering from PDD, where AChE inhibitors are helpful. However, RBC AChE level below the normal where AChE inhibitor may not be effective.

  6. [Anti-cholinesterase activity of dopamine D2 receptor antagonist: its clinical significance].

    Science.gov (United States)

    Mizumoto, A; Itoh, Z

    1989-08-01

    Anti-cholinesterase activity of dopamine D2 receptor antagonist, domperidone was studied by means of chronically implanted force transducers in the gastrointestinal (GI) tract in five conscious dogs. Cisapride was used as a drug to stimulate endogenous release of acetylcholine. In the digestive state, cisapride (0.25 mg/kg) stimulated 18.6 +/- 5.6% increase in the motor index of the gastric antrum alone, however, combined administration with domperidone (1.0 mg/kg-hr) significantly enhanced the motor index in the gastric antrum and duodenum. In the gastric antrum, the increase was 68.1 +/- 7.2%. During the interdigestive state, cisapride did not always induce the interdigestive migrating contractions (IMC)-like contractions in the GI tract, but the background infusion of domperidone significantly increased the incidence of the occurrence of IMC-like contractions by cisapride. In in vitro study, weak but significant anti-cholinesterase activity was found in domperidone, the activity being about 1/1,000 of that of neostigmine. In dog experiment, similar enhancement of motor stimulating activity of cisapride was observed when neostigmine was given at 1.0 micrograms/kg-hr. In conclusion, domperidone has anti-cholinesterase activity and acts to enhance motor stimulating activity of cisapride through inhibition of cholinesterase activity in the upper digestive tract.

  7. Crystal Structure of the Extracellular Cholinesterase-Like Domain from Neuroligin-2

    Energy Technology Data Exchange (ETDEWEB)

    Koehnke,J.; Jin, X.; Budreck, E.; Posy, S.; Scheiffele, P.; Hnoig, B.; Shapiro, L.

    2008-01-01

    Neuroligins (NLs) are catalytically inactive members of a family of cholinesterase-like transmembrane proteins that mediate cell adhesion at neuronal synapses. Postsynaptic neuroligins engage in Ca2+-dependent transsynaptic interactions via their extracellular cholinesterase domain with presynaptic neurexins (NRXs). These interactions may be regulated by two short splice insertions (termed A and B) in the NL cholinesterase domain. Here, we present the 3.3- Angstroms crystal structure of the ectodomain from NL2 containing splice insertion A (NL2A). The overall structure of NL2A resembles that of cholinesterases, but several structural features are unique to the NL proteins. First, structural elements surrounding the esterase active-site region differ significantly between active esterases and NL2A. On the opposite surface of the NL2A molecule, the positions of the A and B splice insertions identify a candidate NRX interaction site of the NL protein. Finally, sequence comparisons of NL isoforms allow for mapping the location of residues of previously identified mutations in NL3 and NL4 found in patients with autism spectrum disorders. Overall, the NL2 structure promises to provide a valuable model for dissecting NL isoform- and synapse-specific functions.

  8. Zectran fed orally to mice...cholinesterase levels in blood determined

    Science.gov (United States)

    Jean Marie Lang; Raymond R. Miskus

    1967-01-01

    Zectran, a carbamate insecticide, is being field-tested against the spruce budworm. Taken in sufficient quantity, it can induce cholinesterase (ChE) inhibition in mammals. In laboratory experiments, Zectran was fed orally to mice. Results indicated that maximum ChE inhibition occurred 15 to 30 minutes after ingestion of Zectran, and that a ChE test is unreliable in the...

  9. The significance of low substrate concentration measurements for mechanistic interpretation in cholinesterases.

    Science.gov (United States)

    Stojan, Jure

    2013-03-25

    Cholinesterases do not follow the Michaelis-Menten kinetics. In the past, many reaction schemes were suggested to explain their complex interactions during the substrate turnover. Covalent catalysis was recognized very early and therefore, double intermediate traditional reaction scheme for the hydrolysis of good substrates at low concentrations was postulated. However, at intermediate and high substrate concentrations homotropic pseudocooperative effects take place in all cholinesterases, due to the nature of their buried active center. In this study, the significance and usefulness of experimental data obtained at low substrate concentrations, where only one substrate molecule accesses the active site at a time, are to be specified for the overall mechanistic evaluations. Indeed, different interpretations are expected when data are processed with equations derived from different reaction schemes. Consequently, the scheme with two substrate binding sites which comprises the structurally evidenced fully occupied active site as ultimate cause for substantially decreased cholinesterase activity at extremely high substrate concentrations is considered here. A special emphasis is put on butyrylcholinesterase, the enzyme with the largest active site among cholinesterases, where the pseudocooperative effects appear at much higher concentrations than in acetylcholinesterases. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  10. Medicinal plants with cholinesterase inhibitory activity: A Review ...

    African Journals Online (AJOL)

    A potential source of AChE and BChE inhibitors is provided by the abundance of plants in nature, and natural products continue to provide useful drugs and templates for the development of other compounds. The present work constitutes a review of the literature on 123 species of medicinal plants that have been tested for ...

  11. Oxime reactivation of erythrocyte cholinesterase inhibited by ethyl p-nitrophenyl ethylphosphonate

    Science.gov (United States)

    Reiner, Elsa

    1965-01-01

    1. Reactivation of erythrocyte cholinesterase inhibited by ethyl p-nitrophenyl ethylphosphonate (armine) was studied with NN′-dimethylenebis-(4-hydroxy-iminomethylpyridinium bromide) (C2-oxime), NN′-trimethylenebis-(4-hydroxy-iminomethylpyridinium bromide) (C3-oxime), NN′-tetramethylene-(4-hydroxy-iminomethylpyridinium bromide) (C4-oxime) and NN′-pentamethylenebis-(4-hydroxyiminomethylpyridinium bromide) (C5-oxime) as reactivators. The kinetics of reactivation were consistent with a reaction of the type: [Formula: see text] and bimolecular rate constants for reactivation were calculated from the corresponding differential equations. 2. Of the four oximes studied C2-oxime was least effective and the other three oximes were about equally effective reactivators. 3. Reactivation of armine-inhibited cholinesterase by C3-oxime was also studied in the presence of substrate. This reaction was first-order with respect to inhibited enzyme, and slower than in the absence of substrate. PMID:5881660

  12. Mechanism of inhibition of cholinesterases by Huperzine A. (Reannouncement with new availability information)

    Energy Technology Data Exchange (ETDEWEB)

    Ashani, Y.; Peggins, J.O.; Doctor, B.P.

    1992-04-30

    Huperzine A, an alkaloid isolated from Huperzia serrata was found to reversibly inhibit acetylcholinesterases (EC 3.1.7) and (EC 3.1.1.8) with i 3.1 on- and off-rates that depend on both the type and the source of enzyme. Long incubation of high concentrations of purified (1-8 PM) with huperzine-A did not show any chemical modification of huperzine-A. A low dissociation constant K sub 1 was obtained for mammalian acetylcholinesterase-huperzine (20-40 nM) compared to mammalian butyrylcholinesterase-huperzine (20-40 microns.) This indicates that the thermodynamic stability of huperzine-cholinesterase complex may depend on the number and type of aromatic amino acid residues in the catalytic pocket region of the cholinesterase molecule.

  13. Cholinesterase Structure: Identification of Mechanisms and Residues Involved in Organophosphate Inhibition and Enzyme Reactivation

    Science.gov (United States)

    2005-05-01

    appreciated. are accelerated. Stabilization of the Sp-methyl group within the This work was a portion of the Ph.D. thesis of Z. K. conducted, in part, at the...of nieso and other prochiral com- (+)-1 (+)2 pounds represents a powerful approach to asymmetric syn- thesis ,[] and a number of enantioselective total...1998). The MacPhee-Quigley, K., Vedvick, T. S., Taylor, P., and Taylor. S. S. presence of cholinesterase in marine algae. Phytochemistry (1986). Profile

  14. The kinetic study of the inhibition of human cholinesterases by demeton-S-methyl shows that cholinesterase-based titration methods are not suitable for this organophosphate.

    Science.gov (United States)

    Bazire, Alexandre; Gillon, Emilie; Lockridge, Oksana; Vallet, Virginie; Nachon, Florian

    2011-04-01

    The organophosphorus insecticide, demeton-S-methyl (DSM), is considered as a good surrogate of the highly toxic nerve agent VX for skin absorption studies due to similar physico-chemical properties and in vitro percutaneous penetration profile. But, when skin distribution was estimated by measuring inhibition of cholinesterase activity, the results were poorly reproducible. The various grades of commercial DSM solutions were suspected to be the origin of the discrepancies. This hypothesis was tested by measuring inhibition of human acetyl- and butyrylcholinesterase by two commercial DSM solutions. The inhibition rate was independent on the enzyme concentration confirming pseudo-first order conditions. But complete inhibition of butyrylcholinesterase activity was achieved only when the DSM concentration was at least 1500-fold higher than the enzyme concentration. Besides, complete inhibition of acetylcholinesterase was never achieved. Mass spectrometry analysis of the inhibited butyrylcholinesterase adducts identified monomethoxyphosphorylated-serine, the aged product of inhibition by DSM or a derivative with a modified leaving group. Neither spontaneous reactivation nor aging of the dimethoxyphosphorylated-serine could account for the inhibition kinetics observed, suggesting an overly complicated kinetic scheme not compatible with the requirement of a titration experiment. In conclusion, cholinesterase-based analytical methods should be avoided for DSM titration in skin penetration studies. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. The effects of inhibition of plasma cholinesterase activity on systemic toxicity and blood catecholamine levels from cocaine infusion in pigs.

    Science.gov (United States)

    Kambam, J; Mets, B; Hickman, R; Janicki, P; James, M F; Kirsch, R

    1993-08-01

    We investigated systemic effects and possible mechanisms for lethality of intravenously infused cocaine in spontaneously breathing and mechanically ventilated unconscious Landrace male pigs weighing about 26 kg (25.75 +/- 0.25 kg) that were pretreated with either saline solution (groups 1 and 3) or iso-ompa (tetraisopropyl pyrophosphoramide), a specific plasma cholinesterase inhibitor (groups 2 and 4). Pigs were made unconscious with sodium thiopental and ventilated with 70% nitrous oxide and 30% oxygen. A carotid arterial cannula and a Swan-Ganz catheter were inserted for hemodynamic monitoring. Pigs in groups 1 and 2 were then allowed to breathe spontaneously and groups 3 and 4 were mechanically ventilated. After obtaining a stable state, as judged by cardiovascular and respiratory parameters, the pigs were infused intravenously with cocaine hydrochloride (0.8 mg/kg/min) until the time of cardiac arrest. Respiratory and cardiovascular parameters, blood temperature, and sodium and potassium levels were monitored. The times of occurrence of respiratory arrests (RA), cardiac arrests (CA), and convulsions were recorded. Our results showed that RA is the primary cause of death in spontaneously breathing pigs and that mechanical ventilation significantly delayed the occurrence of CA (p < 0.05). Significant decreases in cardiac output, mean blood pressure, and heart rate as well as significant increases in systemic and pulmonary vascular resistances, central venous and pulmonary wedge pressures, and blood K+ levels were noted in mechanically ventilated pigs (p < 0.05). Variable hemodynamic responses were noticed in spontaneously breathing pigs. Our results also showed that no significant changes occurred in blood catecholamine levels when compared with baseline values associated with the infusion of toxic doses of cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Acetylcholine muscarinic receptors and response to anti-cholinesterase therapy in patients with Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Derek [Department of Psychiatry, Stobhill Hospital, Glasgow (United Kingdom); Chisholm, Jennifer A.; Patterson, Jim; Wyper, David [Department of Clinical Physics, Southern General Hospital, Glasgow, G51 4TF (United Kingdom); Owens, Jonathan; Pimlott, Sally [Department of Clinical Physics, Western Infirmary, Glasgow (United Kingdom)

    2003-02-01

    An acetylcholine deficit remains the most consistent neurotransmitter abnormality found in Alzheimer's disease and various therapeutic agents have been targeted at this. In this study we investigated the action of Donepezil, a cholinesterase inhibitor that has few side-effects. In particular we set out to investigate whether muscarinic acetylcholine receptor (mAChR) availability influences the response to this therapy. We used the novel single-photon emission tomography (SPET) tracer (R,R)[{sup 123}I]I-quinuclidinyl benzilate (R,R[{sup 123}I]I-QNB), which has high affinity for the M1 subtype of mAChR. Regional cerebral perfusion was also assessed using technetium-99m hexamethylpropylene amine oxime. We investigated 20 patients on Donepezil treatment and ten age-matched controls. The results showed a reduction in (R,R)[{sup 123}I]I-QNB binding in the caudal anterior cingulate in patients compared with controls and relatively high binding in the putamen and rostral anterior cingulate, suggesting a relative sparing of mAChR in these regions. The main finding of the study was that mAChR availability as assessed by (R,R)[{sup 123}I]I-QNB binding did not distinguish responders from non-responders. Interestingly, we found that the extent of cognitive improvement showed no positive correlation with (R,R)[{sup 123}I]I-QNB binding in any brain region but was inversely related to binding in the insular cortex. This suggests that, within the advised cognitive performance band for use of Donepezil, response is greater in those patients with evidence of a more marked cholinergic deficit. A larger study should investigate this. (orig.)

  17. Oral administration of pyridostigmine bromide and huperzine A protects human whole blood cholinesterases from ex vivo exposure to soman.

    Science.gov (United States)

    Gordon, Richard K; Haigh, Julian R; Garcia, Gregory E; Feaster, Shawn R; Riel, Michael A; Lenz, David E; Aisen, Paul S; Doctor, Bhupendra P

    2005-12-15

    Cholinesterases (ChEs) are classified as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) according to their substrate specificity and sensitivity to selected inhibitors. The activities of AChE in red blood cells (RBC-AChE) and BChE in serum can be used as potential biomarkers of suppressed and/or heightened activity in the central and peripheral nervous systems. Exposure to organophosphate (OP) chemical warfare agents (CWAs), pesticides, anesthetics, and a variety of drugs such as cocaine, as well as some neurodegenerative and liver disease states, selectively reduces AChE or BChE activity. In humans, the toxicity of pesticides is well documented. Therefore, blood cholinesterase activity can be exploited as a tool for confirming exposure to these agents and possible treatments. Current assays for measurement of RBC-AChE and serum BChE require several labor-intensive processing steps, suffer from wide statistical variation, and there is no inter-laboratory conversion between methods. These methods, which determine only the serum BChE or RBC-AChE but not both, include the Ellman, radiometric, and deltapH (modified Michel) methods. In contrast, the Walter Reed Army Institute of Research Whole Blood (WRAIR WB, US Patent #6,746,850) cholinesterase assay rapidly determines the activity of both AChE and BChE in unprocessed (uncentrifuged) whole blood, uses a minimally invasive blood sampling technique (e.g., blood from a finger prick), and is semi-automated for high-throughput using the Biomek 2000 robotic system. To date, the WRAIR whole blood assay was used to measure AChE and BChE activities in human blood from volunteers in FDA clinical trials. In the first FDA study, 24 human subjects were given either 30 mg PB orally (n = 19) or placebo (n = 5). Blood samples were obtained pre-dosing and 2.5, 5, 8, and 24 h post-dosing. The samples were analyzed for AChE and BChE activity using the WRAIR WB robotic system, and for PB concentration by HPLC. We found that

  18. Cholinesterase activities and biochemical determinations in patients with prostate cancer: influence of Gleason score, treatment and bone metastasis.

    Science.gov (United States)

    Battisti, Vanessa; Bagatini, Margarete D; Maders, Liési D K; Chiesa, Juarez; Santos, Karen F; Gonçalves, Jamile F; Abdalla, Fátima H; Battisti, Iara E; Schetinger, Maria R C; Morsch, Vera M

    2012-06-01

    Prostate cancer (PCa) is the sixth most common type of cancer worldwide. Cholinesterase is well known as having non-cholinergic functions such as cellular proliferation and differentiation, suggesting a possible influence of cholinesterase in tumorogenesis. Thus, the aim of this study was to investigate the whole blood acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE) activities and some biochemical parameters in PCa patients. This study was performed in 66 PCa patients and 40 control subjects. AChE and BChE activities were determined in PCa patients and the influence of the Gleason score; bone metastasis and treatment in the enzyme activities were also verified. Furthermore, we also analyzed possible biochemical alterations in these patients. AChE and BChE activities decreased in PCa patients in relation to the control group and various biochemical changes were observed in these patients. Moreover, Gleason score, metastasis and treatment influenced cholinesterase activities and biochemical determinations. Our results suggest that cholinesterases activities and biochemical parameters are altered in PCa. These facts support the idea that the drop in the cholinesterase activity and the consequent increased amount of acetylcholine could lead to a cholinergic overstimulation and increase the cell proliferation in PCa. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  19. Pesticide Exposure and Cholinesterase Levels in Migrant Farm Workers in Thailand.

    Science.gov (United States)

    Thetkathuek, Anamai; Yenjai, Pornthip; Jaidee, Wanlop; Jaidee, Patchana; Sriprapat, Poonsak

    2017-01-01

    In this study, we examined the effects of pesticides in migrant farm workers from Cambodia after workplace exposure on fruit plantations in eastern Thailand. We studied 891 migrant farm workers employed on pineapple, durian, and rambutan plantations in Thailand. Data were collected via a detailed questionnaire survey and measurements of serum cholinesterase level (SChE). The majority of subjects was male (57.7%), with an average age of 30.3 years. Most subjects (76.8%) were moderately aware of good industrial hygiene practices. SChE level was divided into four groups based on the results. Only 4.4% had normal levels of cholinesterase activity, 20.5% had slightly reduced levels, 58.5% had markedly reduced levels and were "at risk," and 16.6% who had highest levels of cholinesterase inhibition were deemed to be in an "unsafe" range. SChE was classified into two groups, SChE value of 87.5 was "normal" and workers (95% confidence interval [CI]) was 1.58 (1.14, 2.17). The OR for farm migrant workers who worked on larger plantations of more than 39.5 acres (95% CI) was 2.69 (1.51, 4.82). Finally, the OR for the migrant farm workers who used a backpack sprayer (95% CI) was 2.07 (1.28, 3.34). These results suggest that health screening should be provided to migrant farm workers, especially those who spray pesticides on plantations of >39 acres, use a backpack sprayer, or have a low level of compliance with accepted industrial hygiene practices. These three classes of workers are at increased risk of chemical exposures and developing acute or chronic illness from pesticide exposures.

  20. In vitro antioxidant and anti-cholinesterase activities of Rhizophora mucronata.

    Science.gov (United States)

    Suganthy, N; Devi, K Pandima

    2016-01-01

    Rhizophora mucronata Lam. (Rhizophoraceae), commonly known as Asiatic mangrove, has been used traditionally among Asian countries as folk medicine. This study investigates the cholinesterase inhibitory potential and antioxidant activities of R. mucronata. Rhizophora mucronata leaves were successively extracted using solvents of varying polarity and a dosage of 100-500 µg/ml were used for each assay. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities were assessed according to the method of Ellman. In vitro antioxidant activity was assessed using free radical scavenging, reducing power, and metal-chelating activity (duration - 3 months). Total phenolic and flavonoid content were quantified spectrophotometrically. Compound characterization was done using column chromatography, NMR, FTIR, and LC-MS analysis. Methanolic leaf extract (500 µg/ml) exhibited the highest inhibitory activity against AChE (92.73 ± 0.54%) and BuChE (98.98 ± 0.17%), with an IC50 value of 59.31 ± 0.35 and 51.72 ± 0.33 µg/ml, respectively. Among the different solvent extracts, methanolic extract exhibited the highest antioxidant activity with an IC50 value of 47.39 ± 0.43, 401.45 ± 18.52, 80.23 ± 0.70, and 316.47 ± 3.56 µg/ml for DPPH, hydroxyl, nitric oxide radical, and hydrogen peroxide, respectively. Total polyphenolic and flavonoid contents in methanolic extract were observed to be 598.13 ± 1.85 µg of gallic acid equivalent and 48.85 ± 0.70 μg of rutin equivalent/mg of extract. Compound characterization illustrated (+)-catechin as the bioactive compound responsible for cholinesterase inhibitory and antioxidant activities. The presence of rich source of flavonoids, in particular catechin, might be responsible for its cholinesterase inhibitory and antioxidant activities.

  1. 7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment

    Directory of Open Access Journals (Sweden)

    Jan Korabecny

    2015-12-01

    Full Text Available Alzheimer’s disease (AD is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient’s death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds’ behavior was confirmed in the subsequent molecular modeling studies.

  2. New Acetylcholinesterase Inhibitors for Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Mona Mehta

    2012-01-01

    Full Text Available Acetylcholinesterase (AChE remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

  3. The reactivation effect of pralidoxime in human blood on parathion and paraoxon–induced cholinesterase inhibition

    Directory of Open Access Journals (Sweden)

    Mahvash Jafari

    2006-03-01

    Full Text Available In this investigation the reactivation of cholinesterases by pralidoxime in parathion and paraoxon intoxication in plasma and erythrocytes were studied. For this purpose, human plasma and erythrocytes were incubated with various concentrations of parathion (0.1-10 µM and paraoxon (0.03-0.3 µM at 37 oC for 10 min. Then, pralidoxime (10-300 µM was added to the samples and incubated for 10 min before cholinesterases assay. The results showed that effects of parathion and paraoxon were dose dependent. These agents inhibited more than 85% of butyrylcholinesterase (BChE and acetylcholinesterase (AChE activity and the inhibitory effect of paraoxon was 10 times more than parathion. BChE activity was significantly higher than the control at 100 µM of pralidoxime and it reduced inhibitory effects of parathion to less than 50% and of paraoxon to 42% of control. When pralidoxime (10 µM was added to erythrocytes, the inhibitory effects of two organophosphates were reduced to less than 15%. At higher concentrations of pralidoxime (>100 µM, both BChE and AChE activities were inhibited.

  4. A step toward the reactivation of aged cholinesterases-crystal structure of ligands binding to aged human butyrylcholinesterase

    NARCIS (Netherlands)

    Wandhammer, M.; Koning, M. de; Grol, M. van; Loiodice, M.; Saurel, L.; Noort, D.; Goeldner, M.; Nachon, F.

    2013-01-01

    Organophosphorus nerve agents irreversibly inhibit cholinesterases. Phosphylation of the catalytic serine can be reversed by the mean of powerful nucleophiles like oximes. But the phosphyl adduct can undergo a rapid spontaneous reaction leading to an aged enzyme, i.e., a conjugated enzyme that is no

  5. TIME COURSE OF CHOLINESTERASE INHIBITION IN ADULT RATS TREATED ACUTELY WITH CARBARYL CARBOFURAN, FORMETANATE, METHOMYL, METHIOCARB, OXAMYL ON PROPOXUR.

    Science.gov (United States)

    To compare the toxicity of seven N-methyl carbamates, time course profiles for brain and red blood cell (RBC) cholinesterase (ChE) inhibition were established for each. Adult, male, Long Evans rats (n=4-5 dose group) were dosed orally with either carbaryl (30 mg/kg in corn oil); ...

  6. Characterization of the In Vitro Kinetic Interaction of Chlorpyrifos-Oxon with Rat Salivary Cholinesterase: A Potential Biomonitoring Matrix

    Energy Technology Data Exchange (ETDEWEB)

    Kousba, Ahmed A.(BATTELLE (PACIFIC NW LAB)); Poet, Torka S.(BATTELLE (PACIFIC NW LAB)); Timchalk, Charles (Pacific Northwest National Laboratory)

    2003-02-12

    Chlorpyrifos (CPF) is a commonly used organophosphate insecticide (OP). The primary mechanism of action for CPF involves the inhibition of acetylcholinesterase (AChE) by the active metabolite, CPF-oxon, with subsequent accumulation of acetylcholine (ACh) resulting in a wide range of neutotoxicity. CPF-oxon, can likewise inhibit other non-target cholinesterases (ChE) such as butyrylcholinesterase (BuChE), which represents a detoxification mechanism and a potential biomarker of exposure/response. Biological monitoring for OPs has focused on measuring parent chemical or metabolite in blood and urine or blood ChE inhibition. Salivary biomonitoring has recently been explored as a practical method for examination of chemical exposure; however, there are a limited number of studies exploring its use for OPs. To evaluate the use of salivary ChE as a biological monitor for OP exposure, the current study characterized salivary ChE activity in Sprague-Dawley rats through its comparison with brain and plasma ChE using BW284C51 and iso-OMPA as selective inhibitors of AChE and BuChE, respectively. The study also estimated the kinetic constants describing BuChE interaction with CPF-oxon. A modified Ellman assay in conjunction with pharmacodynamic (PD) modeling was used to characterize the in vitro titration of diluted rat salivary ChE enzyme with CPF-oxon. The results indicated that, more than 95% of rat salivary ChE activity was associated with BuChE activity, total BuChE active site concentration was 0.0012 0.00013 nmol/ml saliva, reactivation rate constant (Kr) was 0.068 0.008 h-1 and inhibitory (Ki) rate constant of 8.825 and 9.80 nM-1h-1 determined experimentally and using model optimization respectively. These study results would be helpful for further evaluating the potential utility of salivary ChE as a practical tool for biological monitor of OP exposures.

  7. Effect of hypochlorite oxidation on cholinesterase-inhibition assay of acetonitrile extracts from fruits and vegetables for monitoring traces of organophosphate pesticides.

    Science.gov (United States)

    Kitamura, Kentaro; Maruyama, Kaori; Hamano, Sachiko; Kishi, Tomohiro; Kawakami, Tsuyoshi; Takahashi, Yasuo; Onodera, Sukeo

    2014-02-01

    A reproducible method for monitoring traces of cholinesterase (ChE) inhibitors in acetonitrile extracts from fruits and vegetables is described. The method is based on hypochlorite oxidation and ChE inhibition assay. Four common representative samples of produce were selected from a supermarket to investigate the effect of different matrices on pesticides recoveries and assay precision. The samples were extracted with acetonitrile to prepare them for ChE inhibition assays: if necessary, clean-up was performed using dispersive solid-phase extraction for gas chromatography-mass spectrometry (GC/MS) analyses. Chlorine was tested as an oxidising reagent for the conversion of thiophosphorus pesticides (P=S compounds) into their P=O analogues, which have high ChE-inhibiting activity. Chlorine consumption of individual acetonitrile extracts was determined and was strongly dependent on the individual types of fruits and vegetables. After treating the acetonitrile extracts with an excess hypochlorite at 25°C for 15 min, the ChE-inhibiting activities and detection limits for each chlorine-treated pesticide solution were determined. Matrix composition did not interfere significantly with the determination of the pesticides. Enhanced anti-ChE activities leading to low detection limits (ppb levels) were observed for the chlorine-treated extracts that were spiked with chlorpyrifos, diazinon, fenitrothion, and isoxathion. This combination of oxidative derivatisation and ChE inhibition assays was used successfully to monitor and perform semi-quantitative determination of ChE inhibitors in apple, tomato, cucumber, and strawberry samples.

  8. Cholinesterase inhibitors and add-on nutritional supplements in Alzheimer's disease: A systematic review of randomized controlled trials

    NARCIS (Netherlands)

    Rijpma, A; Meulenbroek, O.V.; Olde Rikkert, M.G.M.

    2014-01-01

    To date, single drug and nutrient-based interventions have failed to show a clinically relevant effect on Alzheimer's disease (AD). Multidomain interventions may alleviate symptoms and alter the disease course in a synergistic manner. This systematic review examines the effect of adding nutritional

  9. Serum cholinesterase activities distinguish between stroke patients and controls and predict 12-month mortality

    DEFF Research Database (Denmark)

    Ben Assayag, Einor; Shenhar-Tsarfaty, Shani; Ofek, Keren

    2010-01-01

    To date there is no diagnostic biomarker for mild stroke, although elevation of inflammatory biomarkers has been reported at early stages. Previous studies implicated acetylcholinesterase (AChE) involvement in stroke, and circulating AChE activity reflects inflammatory response, since acetylcholi....... For this purpose, serum cholinesterase activities, butyrylcholinesterase-K genotype and inflammatory biomarkers were determined in 264 ischemic stroke patients and matched controls during the acute phase. AChE activities were lower (P......To date there is no diagnostic biomarker for mild stroke, although elevation of inflammatory biomarkers has been reported at early stages. Previous studies implicated acetylcholinesterase (AChE) involvement in stroke, and circulating AChE activity reflects inflammatory response, since acetylcholine...... suppresses inflammation. Therefore, carriers of polymorphisms that modify cholinergic activity should be particularly susceptible to inflammatory damage. Our study sought diagnostic values of AChE and Cholinergic Status (CS, the total capacity for acetylcholine hydrolysis) in suspected stroke patients...

  10. Cholinesterase reactivators: the fate and effects in the organism poisoned with organophosphates/nerve agents.

    Science.gov (United States)

    Bajgar, J; Kuca, K; Jun, D; Bartosova, L; Fusek, J

    2007-12-01

    Understanding the mechanism of action of organophosphates (OP)/nerve agents -- irreversible acetylcholinesterase (AChE, EC 3.1.1.7) inhibition at the cholinergic synapses followed by metabolic dysbalance of the organism -- two therapeutic principles for antidotal treatment are derived. The main drugs are anticholinergics that antagonize the effects of accumulated acetylcholine at the cholinergic synapses and cholinesterase reactivators (oximes) reactivating inhibited AChE. Anticonvulsants such as diazepam are also used to treat convulsions. Though there are experimental data on a good therapeutic effects of reactivators, some attempts to underestimate the role of reactivators as effective antidotes against OP poisoning have been made. Some arguments on the necessity of their administration following OP poisoning are discussed. Their distribution patterns and some metabolic and pharmacological effects are described with the aim to resolve the question on their effective use, possible repeated administration in the treatment of OP poisoning, their peripheral and central effects including questions on their penetration through the blood brain barrier as well as a possibility to achieve their effective concentration for AChE reactivation in the brain. Reactivation of cholinesterases in the peripheral and central nervous system is described and it is underlined its importance for the survival or death of the organism poisoned with OP. Metabolization and some other effects of oximes (not connected with AChE reactivation) are discussed (e.g. forming of the phosphonylated oxime, parasympatholytic action, hepatotoxicity, behavioral changes etc.). An universality of oximes able to reactivate AChE inhibited by all OP is questioned and therefore, needs of development of new oximes is underlined.

  11. Recovery of cholinesterase activity in the earthworm Eisenia fetida Savigny following exposure to chlorpyrifos.

    Science.gov (United States)

    Aamodt, Solveig; Konestabo, Heidi Sjursen; Sverdrup, Line Emilie; Gudbrandsen, Marius; Reinecke, Sophiè A; Reinecke, Adriaan J; Stenersen, Jørgen

    2007-09-01

    Organophosphorus (OP) insecticides inhibit cholinesterase activity, an essential process in the nervous system of most animals. Re-establishment of active enzymes is slow and depends on elimination of the insecticide from the body followed by two lengthy processes: Reactivation and/or biosynthesis of new enzymes. Earthworms (Eisenia fetida) were exposed to either clean or chlorpyrifos-containing (240 mg/kg) soil for 48 h. After transfer to clean soil, we monitored two cholinesterases (E1 and E2) and chlorpyrifos content of the earthworms for 12 weeks. After 14 to 21 d of recovery, the exposed and control worms were indistinguishable in terms of appearance and behavior. Chemical analysis showed a rapid elimination of chlorpyrifos from the earthworms, with only minor levels detected after one week. The activities of E1 and E2 were measured spectrophotometrically in whole specimen homogenates using acetylthiocholine as the substrate. Carbaryl, which selectively inhibits E1, was used to discriminate the enzyme activities. Mean +/- standard error of mean of E1 and E2 activity in the controls immediately after exposure were 1.57 +/- 0.18 nanokatal (nkat)/mg protein (n = 3) and 0.95 +/- 0.07 nkat/mg protein, respectively, and 0.48 +/- 0.07 nkat/mg and 0.45 +/- 0.06 nkat/mg, respectively, in exposed worms. After three weeks, E1 had regained an activity comparable to the controls, whereas E2 remained depressed throughout the 12-week monitoring period. The non- or late recovery of E2 makes this enzyme a potential biomarker candidate for previous OP insecticide exposure in Eisenia fetida, provided the protocol for measurements is improved and standardized.

  12. Poverty, production, and health: inhibition of erythrocyte cholinesterase via occupational exposure to organophosphate insecticides in Chiapas, Mexico.

    Science.gov (United States)

    Tinoco-Ojanguren, R; Halperin, D C

    1998-01-01

    Occupational exposure to organophosphate pesticides and its effects on the concentration of erythrocyte cholinesterase in the rural population of Chiapas, Mexico, are described. The authors surveyed agricultural production and pesticide use was surveyed among 199 campesinos (peasants) in three communities that used various agricultural production systems. The authors measured the concentration of the cholinesterase enzyme in blood samples obtained from 65 campesinos before and after exposure to the insecticide. The authors established a comparison value for the population that was not exposed occupationally. The exposure values of the enzyme concentration were significantly lower than preexposure values (p = .00001) and reference group values (p = .0008). Individuals in the community characterized by subsistence production had significantly lower levels of the enzyme than individuals in the other two communities (p = .01). This result suggested that a greater risk of adverse health effects existed among the poorest communities.

  13. Acute toxicity and cholinesterase inhibition of the nematicide ethoprophos in larvae of gar Atractosteus tropicus(Semionotiformes: Lepisosteidae).

    OpenAIRE

    Mena Torres, Freylan; Pfennig, Sacsha; Arias Andrés, María de Jesús; Márquez-Couturier, Gabriel; Sevilla, Adrián; Protti Q, C. Maurizio

    2012-01-01

    Biomarkers are a widely applied approach in environmental studies. Analyses of cholinesterase (ChE), glutathione S-transferase (GST) and lipid peroxidation (LPO) are biomarkers that can provide information regarding early effects of pollutants at different biochemical levels on an organism. The aim of this study was to evaluate the biomarker approach on a Costa Rican native and relevant species. For this, larvae of gar (Atractosteus tropicus) were exposed to the organophosphorus nematicide, e...

  14. Acute toxicity and cholinesterase inhibition of the nematicide ethoprophos in larvae of gar Atractosteus tropicus (Semionotiformes: Lepisosteidae)

    OpenAIRE

    Freylan Mena Torres; Sascha Pfennig; María de Jesús Arias Andrés; Gabriel Márquez-Couturie; Adrían Sevilla; C. Maurizio Protti Q

    2012-01-01

    Biomarkers are a widely applied approach in environmental studies. Analyses of cholinesterase (ChE), glutathione S-transferase (GST) and lipid peroxidation (LPO) are biomarkers that can provide information regarding early effects of pollutants at different biochemical levels on an organism. The aim of this study was to evaluate the biomarker approach on a Costa Rican native and relevant species. For this, larvae of gar (Atractosteus tropicus) were exposed to the organophosphorus nematicide, e...

  15. A Facile Ionic Liquid Promoted Synthesis, Cholinesterase Inhibitory Activity and Molecular Modeling Study of Novel Highly Functionalized Spiropyrrolidines

    Directory of Open Access Journals (Sweden)

    Abdulrahman I. Almansour

    2015-01-01

    Full Text Available A series of novel dimethoxyindanone embedded spiropyrrolidines were synthesized in ionic liquid, [bmim]Br and were evaluated for their inhibitory activities towards cholinesterases. Among the spiropyrrolidines, compound 4f exhibited the most potent activity with an IC50 value of 1.57 µM against acethylcholinesterase (AChE. Molecular docking simulation for the most active compound was employed with the aim of disclosing its binding mechanism to the active site of AChE receptor.

  16. A facile ionic liquid promoted synthesis, cholinesterase inhibitory activity and molecular modeling study of novel highly functionalized spiropyrrolidines.

    Science.gov (United States)

    Almansour, Abdulrahman I; Kumar, Raju Suresh; Arumugam, Natarajan; Basiri, Alireza; Kia, Yalda; Ali, Mohamed Ashraf; Farooq, Mehvish; Murugaiyah, Vikneswaran

    2015-01-29

    A series of novel dimethoxyindanone embedded spiropyrrolidines were synthesized in ionic liquid, [bmim]Br and were evaluated for their inhibitory activities towards cholinesterases. Among the spiropyrrolidines, compound 4f exhibited the most potent activity with an IC50 value of 1.57 µM against acethylcholinesterase (AChE). Molecular docking simulation for the most active compound was employed with the aim of disclosing its binding mechanism to the active site of AChE receptor.

  17. PON1 status does not influence cholinesterase activity in Egyptian agricultural workers exposed to chlorpyrifos

    Energy Technology Data Exchange (ETDEWEB)

    Ellison, Corie A., E-mail: cellison@buffalo.edu [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Crane, Alice L., E-mail: alcrane@buffalo.edu [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Bonner, Matthew R., E-mail: mrbonner@buffalo.edu [Department of Social and Preventive Medicine, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Knaak, James B., E-mail: jbknaak@aol.com [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Browne, Richard W., E-mail: rwbrowne@buffalo.edu [Department of Biotechnical and Clinical Laboratory Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Lein, Pamela J., E-mail: pjlein@ucdavis.edu [Department of Molecular Biosciences, University of California School of Veterinary Medicine, Davis, CA 95618 (United States); Olson, James R., E-mail: jolson@buffalo.edu [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Department of Social and Preventive Medicine, State University of New York at Buffalo, Buffalo, NY 14214 (United States)

    2012-12-15

    Animal studies have shown that paraoxonase 1 (PON1) genotype can influence susceptibility to the organophosphorus pesticide chlorpyrifos (CPF). However, Monte Carlo analysis suggests that PON1 genotype may not affect CPF-related toxicity at low exposure conditions in humans. The current study sought to determine the influence of PON1 genotype on the activity of blood cholinesterase as well as the effect of CPF exposure on serum PON1 in workers occupationally exposed to CPF. Saliva, blood and urine were collected from agricultural workers (n = 120) from Egypt's Menoufia Governorate to determine PON1 genotype, blood cholinesterase activity, serum PON1 activity towards chlorpyrifos-oxon (CPOase) and paraoxon (POase), and urinary levels of the CPF metabolite 3,5,6-trichloro-2-pyridinol (TCPy). The PON1 55 (P ≤ 0.05) but not the PON1 192 genotype had a significant effect on CPOase activity. However, both the PON1 55 (P ≤ 0.05) and PON1 192 (P ≤ 0.001) genotypes had a significant effect on POase activity. Workers had significantly inhibited AChE and BuChE after CPF application; however, neither CPOase activity nor POase activity was associated with ChE depression when adjusted for CPF exposure (as determined by urinary TCPy levels) and stratified by PON1 genotype. CPOase and POase activity were also generally unaffected by CPF exposure although there were alterations in activity within specific genotype groups. Together, these results suggest that workers retained the capacity to detoxify chlorpyrifos-oxon under the exposure conditions experienced by this study population regardless of PON1 genotype and activity and that effects of CPF exposure on PON1 activity are minimal. -- Highlights: ► CPF exposure resulted in an increase in TCPy and decreases in BuChE and AChE. ► CPOase activity decreased in subjects with the PON1 55LM and PON1 55 MM genotypes. ► Neither PON1 genotype nor CPOase activity had an effect on BuChE or AChE inhibition.

  18. Dihydroagarofuranoid Sesquiterpenes as Acetylcholinesterase Inhibitors from Celastraceae Plants: Maytenus disticha and Euonymus japonicus.

    Science.gov (United States)

    Alarcón, Julio; Cespedes, Carlos L; Muñoz, Evelyn; Balbontin, Cristian; Valdes, Francisco; Gutierrez, Margarita; Astudillo, Luis; Seigler, David S

    2015-12-02

    Natural cholinesterase inhibitors have been found in many biological sources. Nine compounds with agarofuran (epoxyeudesmane) skeletons were isolated from seeds and aerial parts of Maytenus disticha and Euonymus japonicus. The identification and structural elucidation of compounds were based on spectroscopic data analyses. All compounds had inhibitory acetylcholinesterase (AChE) activity. These natural compounds, which possessed mixed or uncompetitive mechanisms of inhibitory activity against AChE, may be considered as models for the design and development of new naturally occurring drugs for management strategies for neurodegenerative diseases. This is the first report of these chemical structures for seeds of M. disticha.

  19. The Effect of Diazinon on Cholinesterase Activity in Plasma and Erythrocytes of Male and Female Rats and the Protective Role of Vitamin E

    Directory of Open Access Journals (Sweden)

    F. Rahimi Anbarkeh

    2015-01-01

    Full Text Available Introduction & Objective: Diazinon (DZN is an organophosphate insecticide that one of the mechanisms of toxicity is the inhibition of cholinesterase. The aim of the present study was to evaluate the effects of diazinon on cholinesterase activity in blood serum and erythrocytes of male and female rats and to assess the protective role of vitamin E. Materials & Methods: In this experimental study, 60 adult wistar rats including 30 male and 30 female rats were selected and divided into 5 groups (n = 6: control group (without any intervention, sham group (received only pure olive oil daily, experimental group 1 (DZN daily, 60 mg/kg, experimental group 2 (received DZN+ vitamin E daily, with the same dose and experimental group 3(received vitamin E daily 200 mg/kg. Diazinon and solvent were injected intraperitoneally and vitamin E was given by gavage. After 2 weeks 3 ml blood was taken from the heart tissue, and titrimetric and Ellman’s method respectively were used for serum and erythrocyte cholinesterases activity assay. Results: In both genders, due to administration of diazinon, we observed significant reduction in serum and erythrocytes cholinesterase activity. The use of vitamin E increased serum and erythrocytes cholinesterase activity in experimental group 2 of female rats but inhibition in erythrocyte and serum cholinesterase activity was not recovered in experimental group 2 of male rats. Conclusion: According to a further reduction of these enzymes activity in female rats with the use of diazinon, it can be concluded that female rats are more sensitive than male rats and it seems that vitamin E as an antioxidants has a protective effect on cholinesterase activity and reduces the toxicity of DZN. (Sci J Hamadan Univ Med Sci 2015; 21 (4:294-303

  20. [ALK inhibitor].

    Science.gov (United States)

    Mano, Hiroyuki

    2011-01-01

    While lung cancer is the leading cause of cancer deaths worldwide, the molecular mechanism underlying its carcinogenesis is mainly unknown. We have discovered a small, fusion-type tyrosine kinase EML4-ALK that is generated through a tiny inversion within the short arm of human chromosome 2. Transgenic mice expressing EML4-ALK in lung developed hundreds of lung cancer nodules soon after birth, but such nodules were readily eradicated upon treatment with an ALK inhibitor. Clinical trials for EML4-ALK-positive lung cancer with an ALK inhibitor is ongoing, with its interim results being highly promising.

  1. Value of Serum Cholinesterase Activity in the Diagnosis of Septic Shock Due to Bacterial Infections.

    Science.gov (United States)

    Bahloul, Mabrouk; Baccouch, Najeh; Chtara, Kamilia; Turki, Mouna; Turki, Olfa; Hamida, Chokri Ben; Chelly, Hedi; Ayedi, Fatma; Chaari, Anis; Bouaziz, Mounir

    2017-06-01

    We aimed to investigate whether serum cholinesterase (SChE) activity can be helpful for the diagnosis of septic shock and to evaluate its usefulness in comparison with procalcitonin (PCT) and C-reactive protein (CRP). A prospective single-blinded study conducted in an intensive care unit of university hospital. Patients were classified as having cardiogenic shock, septic shock, or hemorrhagic shock. We also included a control group without neither hemodynamic instability nor sepsis. For all included patients, SChE, PCT, and CRP were simultaneously sampled. The comparison of sepsis markers between all groups showed that the mean values of PCT and CRP were significantly higher in patients with septic shock. However, SChE activity was significantly lower in this group. The SChE activity was found to be more accurate than PCT and CRP for the diagnosis of septic shock. In fact, an SChE activity ≤ 4000 UI/L predicted the diagnosis of septic shock with a sensitivity of 78%, a specificity of 89%, a predictive negative value of 97%, and a predictive positive value of 65%. However, the prognostic value of SChE activity was poor in multivariate analysis. The SChE activity level was significantly decreased in patients with septic shock. However, its prognostic value is poor. Our results suggest that SChE activity is useful for the diagnosis of septic shock. Further studies are warranted to confirm our findings.

  2. Effect of Seven Newly Synthesized and Currently Available Oxime Cholinesterase Reactivators on Cyclosarin-Intoxicated Rats

    Science.gov (United States)

    Karasova, Jana Zdarova; Kassa, Jiri; Musilek, Kamil; Pohanka, Miroslav; Novotny, Ladislav; Kuca, Kamil

    2009-01-01

    Seven new oxime-based acetylcholinesterase reactivators were compared with three currently available ones (obidoxime, trimedoxime, HI-6) for their ability to lessen cholinesterase inhibition in blood and brain of cyclosarin-treated rats. Oximes were given at doses of 5% their LD50 along with 21 mg/kg atropine five min before the LD50 of cyclosarin (120 ug/kg) was administered. Blood and brain samples were collected 30 minutes later. The greatest difference between acetylcholinesterase inhibition in blood of cyclosarin-treated rats was found after administration of HI-6 (40%), compared to 22% for trimedoxime and 6% for obidoxime. Only two of the seven newly synthesized oximes had any effect (K203 at 7%, K156 at 5%). Effective oximes against cyclosarin-inhibited plasma butyrylcholinesterase were HI-6 (42%), trimedoxime (11%), and K156 (4%). The oximes were less effective in brain than in blood, with reactivation values for HI-6 30% against acetylcholinesterase and 10% against butyrylcholinesterase. Values for newly synthesized oximes were less than 10% for K206, K269 and K203. PMID:19742125

  3. Determination of esterase activity and characterization of cholinesterases in the reef fish Haemulon plumieri.

    Science.gov (United States)

    Leticia, Alpuche-Gual; Gerardo, Gold-Bouchot

    2008-11-01

    White grunt (Haemulon plumieri) has been proposed by the Mesoamerican Barrier Reef System (MBRS) Synoptic Monitoring Program as a bioindicator species. It is in this sense that the present study has a main goal to evaluate this organism's suitability as an indicator species. Individuals were captured during three seasons at the port of Sisal, Yucatan, Mexico which is located in an area that is considered to be weakly impacted by human activities such as agriculture or industry. Both cholinesterase (ChE) and carboxylesterase (CbE) activities were measured in brain, muscle, liver and eye of sampled individuals. Results indicated that ChE and CbE activities were greatest in the brain (256.3 ± 43) and in the liver (191 ± 21), respectively. Furthermore, ChEs detected in brain, liver and muscle were characterized, and results suggested that the acetylcholinesterase (AChE) type was more abundant relative to pseudocholinesterase (BChE) which was rare. In addition, K(m) and V(max) and IC(50) values were calculated from the Michaelis-Menten equation. Finally, an additional experiment in vitro showed a significant decrease in both ChE and CbE activities when different tissues were exposed to model xenobiotics, such as benzo[a]pyrene and Chlorpyrifos. In conclusion, findings from this study confirm the potential suitability of H. plumieri as an organic pollution bioindicator species, and thus of practical use for environmental biomonitoring purposes.

  4. The effects of chlorpyrifos on cholinesterase activity and foraging behavior in the dragonfly, Anax junius (Odonata)

    Science.gov (United States)

    Brewer, S.K.; Atchison, G.J.

    1999-01-01

    We examined head capsule cholinesterase (ChE) and foraging behavior in nymphs of the dragonfly, Anax junius, exposed for 24 h to 0.2, 0.6 and 1.0 ??g l-1 of the organophosphorus (OP) insecticide, chlorpyrifos [O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate]. The invertebrate community is an important component of the structure and function of wetland ecosystems, yet the potential effects of insecticides on wetland ecosystems are largely unknown. Our objectives were to determine if exposure to environmentally realistic concentrations of chlorpyrifos affected foraging behavior and ChE activity in head capsules of dragonfly nymphs. Nymphs were exposed to different concentrations of chlorpyrifos and different prey densities in a factorial design. ChE activities and foraging behaviors of treated nymphs were not statistically different (p ??? 0.05) from control groups. Prey density effects exerted a greater effect on dragonfly foraging than toxicant exposures. Nymphs offered higher prey densities exhibited more foraging behaviors but also missed their prey more often. High variability in ChE activities within the control group and across treated groups precluded determination of relationships between ChE and foraging behaviors. It appears that A. junius is relatively tolerant of chlorpyrifos, although the concentrations we tested have been shown in other work to adversely affect the prey base; therefore the introduction of this insecticide may have indirect adverse affects on top invertebrate predators such as Odonata.

  5. Effects of nonylphenol on cholinesterase and carboxylesterase activities in male guppies (Poecilia reticulata).

    Science.gov (United States)

    Li, Mei-Hui

    2008-11-01

    Compared to the estrogenic effects of 4-nonylphenol (NP), there is little data available on other potential toxic effects of NP in aquatic animals. The effects of NP on cholinesterase (ChE) and carboxylesterase (CbE) activities of male guppies exposed to 10, 60, 150, or 300 μg L(-1) NP were examined after 1, 2, 4, and 7 days of treatment. A significant muscle ChE inhibition, that used acetylthiocholine iodide as a substrate, was noted in male guppies in all NP treatment groups after a 4-day exposure, and 60 and 150 μg L(-1) of NP treatment groups after a 7-day exposure. All guppies exposed to 300 μg L(-1) NP died during the 7-day treatment. However, there was no significant inhibition of muscle ChE that used butyrylthiocholine iodide as a substrate in male guppies for any NP treatments in different exposure times. There were no CbE activity differences in livers of male guppies among NP treatment groups after different exposure times. This is the first report showing the ChE activity inhibition by NP in fish. Further mechanistic studies are needed to define how NP directly or indirectly alters ChE activities at molecular level. The implication of ChE inhibition of NP on potential impacts of aquatic animals also warrants further research.

  6. Butyryl- and acetyl-cholinesterase inhibitory activities in essential oils of Salvia species and their constituents.

    Science.gov (United States)

    Savelev, Sergey U; Okello, Edward J; Perry, Elaine K

    2004-04-01

    Extracts of Salvia (sage) species have been reported to have cholinergic activities relevant to the treatment of Alzheimer's disease. A lack of information on the inhibition of the enzyme butyrylcholinesterase, also considered to be a target in the treatment of the disease, prompted this in vitro investigation of the essential oils of S. fruticosa, S. lavandulaefolia, S. of ficinalis and S. of ficinalis var. purpurea for anti-butyrylcholinesterase activity. Dose-dependent inhibition of human cholinesterases by the extracts and constituents was determined using the method of Ellman. A time dependent increase in the inhibition of butyrylcholinesterase by the oils of S. fruticosa and S. of ficinalis var. purpurea was evident. IC(50) values decreased from 0.15 +/- 0.007 and 0.14 +/- 0.007 mg/mL after 5 min to 0.035 +/- 0.016 and 0.06 +/- 0.018 mg/mL after 90 min incubation time respectively. The slow onset of inhibition of butyrylcholinesterase was also shown by individual constituents, such as 3-carene and beta-pinene. Analyses of the chemical composition of the oils and anti-butyrylcholinesterase activity of their constituents revealed that none of the compounds tested would account for the total activity of the oils and that synergy is likely. Copyright 2004 John Wiley & Sons, Ltd.

  7. Angiogenesis Inhibitors

    Science.gov (United States)

    ... blood vessels “feed” growing tumors with oxygen and nutrients , allowing the cancer cells to invade nearby tissue , to move throughout ... any angiogenesis inhibitors currently being used to treat cancer in humans? Yes. The U.S. Food and Drug Administration (FDA) has approved bevacizumab to ...

  8. Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation.

    Science.gov (United States)

    Panek, Dawid; Więckowska, Anna; Wichur, Tomasz; Bajda, Marek; Godyń, Justyna; Jończyk, Jakub; Mika, Kamil; Janockova, Jana; Soukup, Ondrej; Knez, Damijan; Korabecny, Jan; Gobec, Stanislav; Malawska, Barbara

    2017-01-05

    The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, β-secretase and β-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50 values ranging from 0.83 μM to 19.18 μM. The target compounds displayed inhibition of human β-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 μM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 μM) and inhibitory activity against hBACE1 (33.61% at 50 μM). Compound 52 is a selective AChE inhibitor (IC50 AChE = 6.47 μM) with BACE1 inhibitory activity (26.3% at 50 μM) and it displays the most significant Aβ anti-aggregating properties among all the obtained compounds (39% at 10 μM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. New Structural Scaffolds for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases*

    Science.gov (United States)

    Sit, Rakesh K.; Radić, Zoran; Gerardi, Valeria; Zhang, Limin; Garcia, Edzna; Katalinić, Maja; Amitai, Gabriel; Kovarik, Zrinka; Fokin, Valery V.; Sharpless, K. Barry; Taylor, Palmer

    2011-01-01

    We describe here the synthesis and activity of a new series of oxime reactivators of cholinesterases (ChEs) that contain tertiary amine or imidazole protonatable functional groups. Equilibration between the neutral and protonated species at physiological pH enables the reactivators to cross the blood-brain barrier and distribute in the CNS aqueous space as dictated by interstitial and cellular pH values. Our structure-activity analysis of 134 novel compounds considers primarily imidazole aldoximes and N-substituted 2-hydroxyiminoacetamides. Reactivation capacities of novel oximes are rank ordered by their relative reactivation rate constants at 0.67 mm compared with 2-pyridinealdoxime methiodide for reactivation of four organophosphate (sarin, cyclosarin, VX, and paraoxon) conjugates of human acetylcholinesterase (hAChE). Rank order of the rates differs for reactivation of human butyrylcholinesterase (hBChE) conjugates. The 10 best reactivating oximes, predominantly hydroxyimino acetamide derivatives (for hAChE) and imidazole-containing aldoximes (for hBChE) also exhibited reasonable activity in the reactivation of tabun conjugates. Reactivation kinetics of the lead hydroxyimino acetamide reactivator of hAChE, when analyzed in terms of apparent affinity (1/Kox) and maximum reactivation rate (k2), is superior to the reference uncharged reactivators monoisonitrosoacetone and 2,3-butanedione monoxime and shows potential for further refinement. The disparate pH dependences for reactivation of ChE and the general base-catalyzed oximolysis of acetylthiocholine reveal that distinct reactivator ionization states are involved in the reactivation of ChE conjugates and in conferring nucleophilic reactivity of the oxime group. PMID:21464125

  10. Cholinesterases in development: AChE as a firewall to inhibit cell proliferation and support differentiation.

    Science.gov (United States)

    Layer, Paul G; Klaczinski, Janine; Salfelder, Anika; Sperling, Laura E; Thangaraj, Gopenath; Tuschl, Corina; Vogel-Höpker, Astrid

    2013-03-25

    Acetylcholinesterase (AChE) is a most remarkable protein, not only because it is one of the fastest enzymes in nature, but also since it appears in many molecular forms and is regulated by elaborate genetic networks. AChE is expressed in many tissues during development and in mature organisms, as well as in healthy and diseased states. In search for alternative, "non-classical" functions of cholinesterases (ChEs), AChE could either work within the frame of classic cholinergic systems, but in non-neural tissues ("non-synaptic function"), or act non-enzymatically. Here, we review briefly some of the major ideas and advances of this field, and report on some recent progress from our own experimental work, e.g. that (i) non-neural ChEs have pronounced, predominantly enzymatic effects on early embryonic (limb) development in chick and mouse, that (ii) retinal R28 cells of the rat overexpressing synaptic AChE present a significantly decreased cell proliferation, and that (iii) in developing chick retina ACh-synthesizing and ACh-degrading cells originate from the same postmitotic precursor cells, which later form two locally opposing cell populations. We suggest that such distinct distributions of ChAT(+) vs. AChE(+) cells in the inner half retina provide graded distributions of ACh, which can direct cell differentiation and network formation. Thus, as corroborated by works from many labs, AChE can be considered a highly co-opting protein, which can combine enzymatic and non-enzymatic functions within one molecule. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  11. Relevance of Plasma Cholinesterase to Clinical Findings in Acute Organophosphorous Poisoning

    Directory of Open Access Journals (Sweden)

    Devanur R.M.M. Prasad

    2013-03-01

    Full Text Available Background: Organophosphorus (OP poisoning is a major public health problem in developing world. OP pesticides inhibit carboxylic esterase enzymes including plasma cholinesterase (PChE. Clinical manifestations following OP poisoning can be associated with the extent of decrease of PChE. This study was designed to investigate the relevance of PChE level to clinical manifestations in OP poisoning and to evaluate usefulness of PChE in predicting clinical outcomes. Methods: This was a cross-sectional study which was conducted at Jawaharlal Nehru Medical College, Karnataka from 1st October 2009 to 30th September 2010. Seventy-six OP poisoned patients were enrolled and their clinical manifestations were recorded. 5-ml samples of intravenous blood were collected from each patient (on first day and fifth day of treatment under strict aseptic precaution and the PChE level was measured. Results: In total, mean age of patients were 25.5 (range: 21-30 years. Majority of patients were males (65.7 %, from rural areas (86.84 % and agricultural workers (25%. Main clinical findings at the time of admission were congested conjunctiva (87%, pin point pupil (83%, lacrimation (80%, vomiting (78%, non-reactive pupil (75%, respiratory distress (60% and abdominal pain (37%. Mean (SD PChE at 6 hours post-exposure was 3672.4 (4200.1 IU/L. At presentation, cyanosis, muscle weakness, convulsion, respiratory distress and fasciculation were related to cases with >75%reduction of PChE, while,  constricted and non-reactive pupil, lacrimation and congested conjunctivae were related to cases with 50-75% reduction and abdominal pain, dryness of conjunctiva, vomiting and diarrhea were related to

  12. Treatment with endotracheal therapeutics after sarin microinstillation inhalation exposure increases blood cholinesterase levels in guinea pigs.

    Science.gov (United States)

    Che, Magnus M; Song, Jian; Oguntayo, Samuel; Doctor, Bhupendra P; Rezk, Peter; Perkins, Michael W; Sciuto, Alfred M; Nambiar, Madhusoodana P

    2012-05-01

    Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in the blood and tissues of animals that are treated with a number of endotracheally aerosolized therapeutics for protection against inhalation toxicity to sarin. Therapeutics included, aerosolized atropine methyl bromide (AMB), scopolamine or combination of AMB with salbutamol, sphingosine 1-phosphate, keratinocyte growth factor, adenosine A1 receptor antisense oligonucleotide (EPI2010), 2,3-diacetyloxybenzoic acid (2,3 DABA), oxycyte, and survanta. Guinea pigs exposed to 677.4 mg/m(3) or 846.5 mg/m(3) (1.2 LCt(50)) sarin for 4 min using a microinstillation inhalation exposure technique and treated 1 min later with the aerosolized therapeutics. Treatment with all therapeutics significantly increased the survival rate with no convulsions throughout the 24 h study period. Blood AChE activity determined using acetylthiocholine as substrate showed 20% activity remaining in sarin-exposed animals compare to controls. In aerosolized AMB and scopolamine-treated animals the remaining AChE activity was significantly higher (45-60%) compared to sarin-exposed animals (p treatment with all the combination therapeutics resulted in significant increase in blood AChE activity in comparison to sarin-exposed animals although the increases varied between treatments (p treatment with aerosolized therapeutics but was lesser in magnitude compared to AChE activity changes. Various tissues showed elevated AChE activity after therapeutic treatment of sarin-exposed animals. Increased AChE and BChE activities in animals treated with nasal therapeutics suggest that enhanced breathing and reduced respiratory toxicity/lung injury possibly contribute to rapid normalization of chemical warfare nerve agent inhibited cholinesterases.

  13. In Vitro Cysteine Reactivates Organophosphate Insecticide Dichlorvos-Inhibited Human Cholinesterases

    Directory of Open Access Journals (Sweden)

    Hamidreza Mohammadi

    2017-08-01

    Full Text Available Objectives: Organophosphate (OP pesticides inhibit both red blood cell (RBC and plasma cholinesterases (ChEs. Oximes, especially pralidoxime (2-PAM, are widely used as antidotes to treat OP poisoning. In addition, N-acetylcysteine (NAC is sometimes used as an adjuvant antidote. The current study aimed to assess the feasibility of using NAC as a single therapeutic agent for OP poisoning in comparison to in vitro 2-PAM. Methods:This study was carried out at the Razi Drug Research Center of Iran University of Medical Sciences, Tehran, Iran, between April and September 2014. A total of 22 healthy human subjects were recruited and 8 mL citrated blood samples were drawn from each subject. Dichlorvos-inhibited blood samples were separately exposed to low and high doses (final concentrations of 300 and 600 μmol.L-1, respectively of 2-PAM, NAC and cysteine. Plasma and RBCs were then separated by centrifugation and their ChE activity was measured using spectrophotometry. Results: Although cysteine—and not NAC—increased the ChE activity of both plasma and RBCs over those of dichlorvos, it did not increase them over those of a high dose of 2-PAM. Conclusion:These results suggest that the direct reactions of 2-PAM and cysteine with dichlorvos and the reactivation of phosphorylated ChEs occurr via an associative stepwise addition-elimination process. High therapeutic blood concentrations of cysteine are needed for the elevation of ChE activity in plasma and RBCs; however, both this agent and NAC may still be effective in the reactivation of plasma and RBC ChEs.

  14. Effect of pomegranate extracts on brain antioxidant markers and cholinesterase activity in high fat-high fructose diet induced obesity in rat model.

    Science.gov (United States)

    Amri, Zahra; Ghorbel, Asma; Turki, Mouna; Akrout, Férièle Messadi; Ayadi, Fatma; Elfeki, Abdelfateh; Hammami, Mohamed

    2017-06-27

    To investigate beneficial effects of Pomegranate seeds oil (PSO), leaves (PL), juice (PJ) and (PP) on brain cholinesterase activity, brain oxidative stress and lipid profile in high-fat-high fructose diet (HFD) induced-obese rat. In vitro and in vivo cholinesterase activity, brain oxidative status, body and brain weight and plasma lipid profile were measured in control rats, HFD-fed rats and HFD-fed rats treated by PSO, PL, PJ and PP. In vitro study showed that PSO, PL, PP, PJ inhibited cholinesterase activity in dose dependant manner. PL extract displayed the highest inhibitory activity by IC50 of 151.85 mg/ml. For in vivo study, HFD regime induced a significant increase of cholinesterase activity in brain by 17.4% as compared to normal rats. However, the administration of PSO, PL, PJ and PP to HDF-rats decreased cholinesterase activity in brain respectively by 15.48%, 6.4%, 20% and 18.7% as compared to untreated HFD-rats. Moreover, HFD regime caused significant increase in brain stress, brain and body weight, and lipid profile disorders in blood. Furthermore, PSO, PL, PJ and PP modulated lipid profile in blood and prevented accumulation of lipid in brain and body evidenced by the decrease of their weights as compared to untreated HFD-rats. In addition administration of these extract protected brain from stress oxidant, evidenced by the decrease of malondialdehyde (MDA) and Protein carbonylation (PC) levels and the increase in superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. These findings highlight the neuroprotective effects of pomegranate extracts and one of mechanisms is the inhibition of cholinesterase and the stimulation of antioxidant capacity.

  15. Brain cholinesterase response in the snakehead fish (Channa striata) after field exposure to diazinon

    DEFF Research Database (Denmark)

    van Cong, Nguyen; Phuong, Nguyen Thanh; Bayley, Mark

    2008-01-01

    commonly used chemicals in rice paddies. In the present study, exposure of adult snakehead fish to a single diazinon application in cages within a rice field resulted in long-term brain cholinesterase inhibition, while the water concentration of this insecticide fell below the detection limit within 3 days......The snakehead Channa striata is an economically important air-breathing fish species in the Mekong delta of Vietnam. Rice paddies, which are disturbed by the frequent application of agro-chemicals, are among the preferred habitats for this species during the rainy season. Diazinon is one of most...

  16. A facile chemo-, regio- and stereoselective synthesis and cholinesterase inhibitory activity of spirooxindole-pyrrolizine-piperidine hybrids.

    Science.gov (United States)

    Kia, Yalda; Osman, Hasnah; Kumar, Raju Suresh; Murugaiyah, Vikneswaran; Basiri, Alireza; Perumal, Subbu; Razak, Ibrahim Abdul

    2013-05-15

    A series of novel hybrid spiro heterocycles comprising pyrrolizine, spiroxindole and piperidine moieties was synthesized chemo-, regio- and stereoselectively in good yields from 1,3-dipolar cycloaddition reaction of a series of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with azomethine ylides generated in situ from 5-choloroisatin and l-proline in methanol. These cycloadducts displayed significant cholinesterase inhibitory activity. Among the compounds screened, 8g and 8e, showed maximum inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinestrase (BChE) with IC50 values of 3.33 and 3.13μM, respectively. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Rosemary tea consumption results to anxiolytic- and anti-depressant-like behavior of adult male mice and inhibits all cerebral area and liver cholinesterase activity; phytochemical investigation and in silico studies.

    Science.gov (United States)

    Ferlemi, Anastasia-Varvara; Katsikoudi, Antigoni; Kontogianni, Vassiliki G; Kellici, Tahsin F; Iatrou, Grigoris; Lamari, Fotini N; Tzakos, Andreas G; Margarity, Marigoula

    2015-07-25

    Our aim was to investigate the possible effects of regular drinking of Rosmarinus officinalis L. leaf infusion on behavior and on AChE activity of mice. Rosemary tea (2% w/w) phytochemical profile was investigated through LC/DAD/ESI-MS(n). Adult male mice were randomly divided into two groups: "Rosemary-treated" that received orally the rosemary tea for 4weeks and "control" that received drinking water. The effects of regular drinking of rosemary tea on behavioral parameters were assessed by passive avoidance, elevated plus maze and forced swimming tests. Moreover, its effects on cerebral and liver cholinesterase (ChE) isoforms activity were examined colorimetricaly. Phytochemical analysis revealed the presence of diterpenes, flavonoids and hydroxycinnamic derivatives in rosemary tea; the major compounds were quantitatively determined. Its consumption rigorously affected anxiety/fear and depression-like behavior of mice, though memory/learning was unaffected. ChE isoforms activity was significantly decreased in brain and liver of "rosemary treated" mice. In order to explain the tissue ChE inhibition, principal component analysis, pharmacophore alignment and molecular docking were used to explore a possible relationship between main identified compounds of rosemary tea, i.e. rosmarinic acid, luteolin-7-O-glucuronide, caffeic acid and known AChE inhibitors. Results revealed potential common pharmacophores of the phenolic components with the inhibitors. Our findings suggest that rosemary tea administration exerts anxiolytic and antidepressant effects on mice and inhibits ChE activity; its main phytochemicals may function in a similar way as inhibitors. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. Comparison of cholinesterase activities in the excretion-secretion products of Trichinella pseudospiralis and Trichinella spiralis muscle larvae

    Directory of Open Access Journals (Sweden)

    Ros-Moreno R.M.

    2002-06-01

    Full Text Available The presence of cholinesterases (ChE is reported in T. pseudospiralis excretion-secretion products (ESP by spectrophotometry method, using acetylthiocholine (ATCI and butyrilthiocholine (BTCI as substrates. By inhibition assays, we found that T. pseudospiralis release both acetyl- and butiryl-cholinesterases (AchE and BchE, respectively. The sedimentation coefficientes of these enzymes were determined by sucrose density gradient. We studied the in vivo ChE secretion by immunoblot assays using AchE from Electrophorus (electric eel and sera from normal or infected mice with T. pseudospiralis or T. spiralis. The presence of anti-AchE antibodies was only demonstrated in the sera from T. pseudospiralis infected mice. Moreover the in vivo secretion was corroborated by the high difference determinate between the ChE activity of the immuno complexes from T. pseudospiralis infected sera and the immunocomplexes from T. spiralis infected sera as well as normal sera. Finally, we analyzed the effect of the organophosphate NeguvónR (metrifonate on the ChE activity from the J. pseudospiralis ESP. The drug inhibits in part this activity. Moreover NeguvónR (metrifonate showed a high activity against the T. pseudospiralis viability.

  19. Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes.

    Science.gov (United States)

    Suemizu, Hiroshi; Sota, Shigeto; Kuronuma, Miyuki; Shimizu, Makiko; Yamazaki, Hiroshi

    2014-11-01

    Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Phytochemical profile of a blend of black chokeberry and lemon juice with cholinesterase inhibitory effect and antioxidant potential.

    Science.gov (United States)

    Gironés-Vilaplana, Amadeo; Valentão, Patrícia; Andrade, Paula B; Ferreres, Federico; Moreno, Diego A; García-Viguera, Cristina

    2012-10-15

    In this study, black chokeberry concentrate was added (5% w/v) to lemon juice, since previous reports suggested potential health benefits of this blend. The phytochemical composition, antioxidant capacity (scavenging of DPPH, superoxide and hydroxyl radicals, and hypochlorous acid), and inhibitory activity against cholinesterase of the new blend were determined and compared with those of lemon juice and chokeberry in citric acid (5%). The chokeberry concentrate, rich in cyanidin-glycosides, quercetin derivatives, and 3-O-caffeoylquinic acid, and lemon juice, possessing flavones, flavanones, quercetin derivates, and hydroxycinnamic acids, were characterised. The new drink showed a higher antioxidant effect than the chokeberry or lemon controls for all the tested methods, except for hypochlorous acid, in which lemon juice displayed higher activity. Both the lemon juice and chokeberry controls inhibited acetylcholinesterase and butyrylcholinesterase, and this effect was increased in the new mixtures. The results of the different radical scavenging assays indicate that the lemon-black chokeberry (5% w/v) mixture was more antioxidative than the respective controls separately. Moreover, their inhibition of cholinesterase is of interest regarding neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, or senile dementia. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Cholinesterases as scavengers for organophosphorus compounds: Protection of primate performance against soman toxicity. (Reannouncement with new availability information)

    Energy Technology Data Exchange (ETDEWEB)

    Doctor, B.P.; Blick, D.W.; Caranto, G.; Castro, C.A.; Gentry, M.K.

    1993-12-31

    The present treatment for poisoning by organophosphates consists of multiple drugs such as carbamates, antimuscarinics, and reactivators in pre- and post-exposure modalities. Recently an anticonvulsant, diazapam, has been included as a post-exposure drug to reduce convulsions and increase survival. Most regimens are effective in preventing lethality from organophosphate exposure but do not prevent toxic effects and incapacitation observed in animals and likely to occur in humans. Use of enzymes such as cholinesterases as pretreatment drugs for sequestration of highly toxic organophosphate anticholinesterases and alleviation of side effects and performance decrements was successful in animals, including non-human primates. Pretreatment of rhesus monkeys with fetal bovine serum acetyleholinesterase protected them against lethal effects of soman (up to 5 LD50) and prevented signs of OP toxicity. Monkeys pretreated with fetal bovine serum acetylcholinesterase were devoid of behavioral incapacitation after soman exposure, as measured by serial probe recognition or primate equilibrium platform performance tasks. Use of acetylcholinesterase as a single pretreatment drug provided greater protection against both lethal and behavioral effects of potent organophosphates than current multicomponent drug treatments that prevent neither signs of toxicity nor behavioral deficits. Cholinesterases, Pretreatment, Toxicity, Organophosphates, Soman, Scavengers.

  2. Annual Interviews

    CERN Multimedia

    Human Resources Department

    2005-01-01

    Annex II, page 1, Section 3 of the Administrative Circular no. 26 (Rev. 5) states that "The annual interview shall usually take place between 15 November of the reference year and 15 February of the following year." Following the meeting of the Executive Board on 7 December 2004 and the meeting of the Standing Concertation Committee on 19 January 2005, it has been decided, for the advancement exercise of 2005, to extend this period until 15 March 2005. Human Resources Department Tel. 73566

  3. Association between arsenic exposure and plasma cholinesterase activity: a population based study in Bangladesh

    Directory of Open Access Journals (Sweden)

    Karim Md Rezaul

    2010-07-01

    Full Text Available Abstract Background Arsenic is a potent pollutant that has caused an environmental catastrophe in certain parts of the world including Bangladesh where millions of people are presently at risk due to drinking water contaminated by arsenic. Chronic arsenic exposure has been scientifically shown as a cause for liver damage, cancers, neurological disorders and several other ailments. The relationship between plasma cholinesterase (PChE activity and arsenic exposure has not yet been clearly documented. However, decreased PChE activity has been found in patients suffering liver dysfunction, heart attack, cancer metastasis and neurotoxicity. Therefore, in this study, we evaluated the PChE activity in individuals exposed to arsenic via drinking water in Bangladesh. Methods A total of 141 Bangladeshi residents living in arsenic endemic areas with the mean arsenic exposure of 14.10 ± 3.27 years were selected as study subjects and split into tertile groups based on three water arsenic concentrations: low ( 265 μg/L. Study subjects were further sub-divided into two groups (≤50 μg/L and > 50 μg/L based on the recommended upper limit of water arsenic concentration (50 μg/L in Bangladesh. Blood samples were collected from the study subjects by venipuncture and arsenic concentrations in drinking water, hair and nail samples were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS. PChE activity was assayed by spectrophotometer. Results Arsenic concentrations in hair and nails were positively correlated with the arsenic levels in drinking water. Significant decreases in PChE activity were observed with increasing concentrations of arsenic in water, hair and nails. The average levels of PChE activity in low, medium and high arsenic exposure groups were also significantly different between each group. Lower levels of PChE activity were also observed in the > 50 μg/L group compared to the ≤50 μg/L group. Moreover, PChE activity was

  4. Genomic analysis of carboxyl/cholinesterase genes in the silkworm Bombyx mori

    Directory of Open Access Journals (Sweden)

    Shiotsuki Takahiro

    2010-06-01

    Full Text Available Abstract Background Carboxyl/cholinesterases (CCEs have pivotal roles in dietary detoxification, pheromone or hormone degradation and neurodevelopment. The recent completion of genome projects in various insect species has led to the identification of multiple CCEs with unknown functions. Here, we analyzed the phylogeny, expression and genomic distribution of 69 putative CCEs in the silkworm, Bombyx mori (Lepidoptera: Bombycidae. Results A phylogenetic tree of CCEs in B. mori and other lepidopteran species was constructed. The expression pattern of each B. mori CCE was also investigated by a search of an expressed sequence tag (EST database, and the relationship between phylogeny and expression was analyzed. A large number of B. mori CCEs were identified from a midgut EST library. CCEs expressed in the midgut formed a cluster in the phylogenetic tree that included not only B. mori genes but also those of other lepidopteran species. The silkworm, and possibly also other lepidopteran species, has a large number of CCEs, and this might be a consequence of the large cluster of midgut CCEs. Investigation of intron-exon organization in B. mori CCEs revealed that their positions and splicing site phases were strongly conserved. Several B. mori CCEs, including juvenile hormone esterase, not only showed clustering in the phylogenetic tree but were also closely located on silkworm chromosomes. We investigated the phylogeny and microsynteny of neuroligins in detail, among many CCEs. Interestingly, we found the evolution of this gene appeared not to be conserved between B. mori and other insect orders. Conclusions We analyzed 69 putative CCEs from B. mori. Comparison of these CCEs with other lepidopteran CCEs indicated that they had conserved expression and function in this insect order. The analyses showed that CCEs were unevenly distributed across the genome of B. mori and suggested that neuroligins may have a distinct evolutionary history from other

  5. In vitro antioxidant and cholinesterase inhibitory activities of methanolic fruit extract of Phyllanthus acidus.

    Science.gov (United States)

    Moniruzzaman, Md; Asaduzzaman, Md; Hossain, Md Sarwar; Sarker, Jyotirmoy; Rahman, S M Abdur; Rashid, Mamunur; Rahman, Md Mosiqur

    2015-11-09

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder clinically characterized by loss of memory and cognition. Cholinergic deficit and oxidative stress have been implicated in the pathogenesis of AD. Therefore, inhibition of acetylcholinesterase and oxidation are the two promising strategies in the development of drug for AD. Phyllanthus acidus, belonging to the family Euphorbiaceae, is a tree and has been used in traditional medicine to treat several pain, inflammatory and oxidative stress related disorders such as rheumatism, bronchitis, asthma, respiratory disorder, also important to promote intellect and enhance memory, thus supporting its possible anti-Alzheimer's properties. In this study, P. acidus was evaluated for its cholinesterase inhibitory and antioxidant activities. In this study, we evaluated the antioxidant potential and neuroprotective activity of P. acidus by assessing total phenol content (FCR assay), total flavonoid content, total antioxidant capacity, Fe (3+) reducing power capacity, DPPH (2, 2-diphenyl-1-picrylhydrazyl) and hydroxyl radical scavenging capacity, lipid peroxidation inhibition activity & metal chelating activity. In addition acetylcholinestrase (AChE) and butyrylcholinestrase (BChE) inhibitory activities were performed using Ellman's method. Total phenolic content and total flavonoid content of the extract were 116.98 mg of gallic acid equivalent and 168.24 mg of quercetin equivalent per gm of dried extract. The methanolic extract of P. acidus (MEPA) showed considerable total antioxidant activity and reducing capacity. In DPPH scavenging assay and hydroxyl radical scavenging assay, the MEPA showed 84.33 % and 77.21 % scavenging having IC50 of 15.62 and 59.74 μg/ml respectively. In lipid peroxidation inhibition activity MEPA showed moderate inhibition of peroxidation at all concentrations with IC50 value of 471.63 μg/ml and exhibited metal chelating activity with IC50 value 308.67 μg/ml. The MEPA exhibited

  6. Association between arsenic exposure and plasma cholinesterase activity: a population based study in Bangladesh.

    Science.gov (United States)

    Ali, Nurshad; Hoque, Md Ashraful; Haque, Abedul; Salam, Kazi Abdus; Karim, Md Rezaul; Rahman, Aminur; Islam, Khairul; Saud, Zahangir Alam; Khalek, Md Abdul; Akhand, Anwarul Azim; Hossain, Mostaque; Mandal, Abul; Karim, Md Rezaul; Miyataka, Hideki; Himeno, Seiichiro; Hossain, Khaled

    2010-07-10

    Arsenic is a potent pollutant that has caused an environmental catastrophe in certain parts of the world including Bangladesh where millions of people are presently at risk due to drinking water contaminated by arsenic. Chronic arsenic exposure has been scientifically shown as a cause for liver damage, cancers, neurological disorders and several other ailments. The relationship between plasma cholinesterase (PChE) activity and arsenic exposure has not yet been clearly documented. However, decreased PChE activity has been found in patients suffering liver dysfunction, heart attack, cancer metastasis and neurotoxicity. Therefore, in this study, we evaluated the PChE activity in individuals exposed to arsenic via drinking water in Bangladesh. A total of 141 Bangladeshi residents living in arsenic endemic areas with the mean arsenic exposure of 14.10 +/- 3.27 years were selected as study subjects and split into tertile groups based on three water arsenic concentrations: low ( 265 microg/L). Study subjects were further sub-divided into two groups ( 50 microg/L) based on the recommended upper limit of water arsenic concentration (50 microg/L) in Bangladesh. Blood samples were collected from the study subjects by venipuncture and arsenic concentrations in drinking water, hair and nail samples were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). PChE activity was assayed by spectrophotometer. Arsenic concentrations in hair and nails were positively correlated with the arsenic levels in drinking water. Significant decreases in PChE activity were observed with increasing concentrations of arsenic in water, hair and nails. The average levels of PChE activity in low, medium and high arsenic exposure groups were also significantly different between each group. Lower levels of PChE activity were also observed in the > 50 microg/L group compared to the

  7. Effects of Agricultural Management Policies on the Exposure of Black-Winged Stilts (Himantopus himantopus Chicks to Cholinesterase-Inhibiting Pesticides in Rice Fields.

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    Gregorio M Toral

    Full Text Available Levels of exposure to pesticides in rice fields can be significant depending on the environmental policies practiced. The aim of European Union integrated management policy is to reduce pesticide use and impact on environment. Rice fields provide an alternative breeding habitat for many waterbirds that are exposed to the pesticides used and therefore can be valuable indicators of their risk for wildlife. To evaluate integrated management success we examined exposure of Black-winged Stilts (Himantopus himantopus to cholinesterase-inhibiting pesticides in rice fields under different types of management by measuring plasma cholinesterase activity. Cholinesterase activity was lower in birds sampled in (a 2008 after a period of intense pesticide application, than in (b 2005-2007 and 2011 in rice fields subject to integrated management in Doñana (SW Spain and (c in control natural wetlands in Spain and Morocco. During 2009 and 2010, cholinesterase activity was lower in rice fields in Doñana than in rice fields in Larache and Sidi Allal Tazi (NW Morocco. Our results suggest that integrated management successfully reduced the exposure of Black-winged Stilts to pesticides in most of the years. Care should be taken to implement mosquito and pest crop controls on time and with environmentally friendly products in order to reduce its impact on wildlife.

  8. DEPRESSION OF THE PHOTIC AFTER DISCHARGE OF FLASH EVOKED POTENTIALS BY PHYSOSTIGMINE, CARBARYL AND PROPOXUR AND THE RELATIONSHIP TO INHIBITION OF BRAIN CHOLINESTERASE

    Science.gov (United States)

    The effects of N-methyl carbamate pesticides on the photic after discharge (PhAD) of flash evoked potentials (FEPs) and the relationship between inhibition of brain cholinesterase (ChE) activity and the PhAD were evaluated. FEPs were recorded in Long Evans rats treated with physo...

  9. Organophosphate insecticides target the serotonergic system in developing rat brain regions: disparate effects of diazinon and parathion at doses spanning the threshold for cholinesterase inhibition.

    Science.gov (United States)

    Slotkin, Theodore A; Tate, Charlotte A; Ryde, Ian T; Levin, Edward D; Seidler, Frederic J

    2006-10-01

    In the developing brain, serotonin (5HT) systems are among the most sensitive to disruption by organophosphates. We exposed neonatal rats to daily doses of diazinon or parathion on postnatal days (PND)1-4 and evaluated 5HT receptors and the 5HT transporter in brainstem and forebrain on PND5, focusing on doses of each agent below the maximum tolerated dose and spanning the threshold for cholinesterase inhibition: 0.5, 1, or 2 mg/kg for diazinon, and 0.02, 0.05, and 0.1 mg/kg for parathion. Diazinon evoked up-regulation of 5HT1A and 5HT2 receptor expression even at doses devoid of effects on cholinesterase activity, a pattern similar to that seen earlier for another organophosphate, chlorpyrifos. In contrast, parathion decreased 5HT1A receptors, again at doses below those required for effects on cholinesterase. The two agents also differed in their effects on the 5HT transporter. Diazinon evoked a decrease in the brainstem and an increase in the forebrain, again similar to that seen for chlorpyrifos; this pattern is typical of damage of nerve terminals and reactive sprouting. Parathion had smaller, nonsignificant effects. Our results buttress the idea that, in the developing brain, the various organophosphates target specific neurotransmitter systems differently from each other and without the requirement for cholinesterase inhibition, their supposed common mechanism of action.

  10. Differential acetyl cholinesterase inhibition by volatile oils from two specimens of Marlierea racemosa (Myrtaceae) collected from different areas of the Atlantic Rain Forest.

    Science.gov (United States)

    Souza, Amanda; Silva, Michelle C; Cardoso-Lopes, Elaine M; Cordeiro, Inês; Sobral, Marcos E G; Young, Maria Cláudia M; Moreno, Paulo R H

    2009-08-01

    The volatile oil composition and anti-acetyl cholinesterase activity were analyzed in two specimens of Marlierea racemosa growing in different areas of the Atlantic Rain Forest (Cananéia and Caraguatatuba, SP, Brazil). Component identifications were performed by GC/MS and their acetyl cholinesterase inhibitory activity was measured through colorimetric analysis. The major constituent in both specimens was spathulenol (25.1% in Cananéia and 31.9% in Caraguatatuba). However, the first one also presented monoterpenes (41.2%), while in the Carguatatuba plants, this class was not detected. The oils from the plants collected in Cananéia were able to inhibit the acetyl cholinesterase activity by up to 75%, but for oils from the other locality the maximal inhibition achieved was 35%. These results suggested that the monoterpenes are more effective in the inhibition of acetyl cholinesterase activity than sesquiterpenes as these compounds are present in higher amounts in the M. racemosa plants collected in Cananéia.

  11. Cholinesterase Inhibition and Depression of the Photic After Discharge of Flash Evoked Potentials Following Acute or Repeated Exposures to a Mixture of Carbaryl and Propoxur

    Science.gov (United States)

    While information exists regarding inhibition of cholinesterase (ChE) activity, little is known about neurophysiological changes produced by a mixture of N-methyl carbamate pesticides. Previously, we reported that acute treatment with propoxur or carbaryl decreased the duration o...

  12. Colinesterasas eritrocitaria y plasmática en trabajadores con enfermedades crónicas controladas y en usuarios de medicamentos Erythrocytic and plasmatic cholinesterases in workers with chronic controlled diseases and in users of medicines

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    Jaime Carmona Fonseca

    2006-01-01

    nunca hubo diferencia significativa. Tampoco hubo diferencias importan-tes cuando se procedió a comparar los valores enzimáticos entre personas con una enfermedad específica y quienes no la tenían, excepto en el caso de «anemia». CONCLUSIONES: los niveles de colinesterasas eritrocitaria y plasmática son similares entre trabajadores sanos o con enfermedades crónicas controladas, con o sin drogas. PROBLEM: Physiological values of cholinesterase are known in healthy population, but limited information on them is available in individuals with chronic, controlled diseases, either with or without medication. OBJECTIVES: To measure erythrocytic and plasmatic cholinesterase levels in active workers who met the following conditions: to be feeling well and active at their jobs at the time of the study; to suffer from some disease that was under control either with or without medication; not to have been exposed to pesticides based on cholinesterase inhibitors. METHODOLOGY: A survey was carried out among workers affiliated to the Social Security Institute in Antioquia, Colombia, to identify those suffering from some disease and who had it under control. Acetylcholinesterase and butyrylcholinesterase levels were determined using two techniques for the former and three for the latter. Surveyed workers belonged to two different parts of Antioquia, namely: the Aburra Valley and the Near East region. The study sample was made up by 827 persons, 19% of which informed to be suffering from some disease. RESULTS: Prevalence of disease in the Aburra Valley workers was 30% and in those from the Near East region, 9% (p = 0.0000000. The list of their diseases included 13 different ones, the most frequent of which were: hypertension (29%, “liver disease” (16%, anemia (10%, and arthritis (10%. Out of the 827 people, 127 (15% were under some kind of medication at the moment of the study; of them, 85% were being treated with only one drug. Eight per cent were diseased and under

  13. Effects of cholinesterase inhibiting sage (Salvia officinalis) on mood, anxiety and performance on a psychological stressor battery.

    Science.gov (United States)

    Kennedy, David O; Pace, Sonia; Haskell, Crystal; Okello, Edward J; Milne, Anthea; Scholey, Andrew B

    2006-04-01

    Salvia officinalis (sage) has previously been shown both to possess in vitro cholinesterase inhibiting properties, and to enhance mnemonic performance and improve mood in healthy young participants. In this double-blind, placebo-controlled, crossover study, 30 healthy participants attended the laboratory on three separate days, 7 days apart, receiving a different treatment in counterbalanced order on each occasion (placebo, 300, 600 mg dried sage leaf). On each day mood was assessed predose and at 1 and 4 h postdose. Each mood assessment comprised completion of Bond-Lader mood scales and the State Trait Anxiety Inventory (STAI) before and after 20 min performance of the Defined Intensity Stress Simulator (DISS) computerized multitasking battery. In a concomitant investigation, an extract of the sage leaf exhibited dose-dependent, in vitro inhibition of acetylcholinesterase and, to a greater extent, butyrylcholinesterase. Both doses of sage led to improved ratings of mood in the absence of the stressor (that is, in pre-DISS mood scores) postdose, with the lower dose reducing anxiety and the higher dose increasing 'alertness', 'calmness' and 'contentedness' on the Bond-Lader mood scales. The reduced anxiety effect following the lower dose was, however, abolished by performing the DISS, with the same dose also being associated with a reduction of alertness during performance. Task performance on the DISS battery was improved for the higher dose at both postdose sessions, but reduced for the lower dose at the later testing session. The results confirm previous observations of the cholinesterase inhibiting properties of S. officinalis, and improved mood and cognitive performance following the administration of single doses to healthy young participants.

  14. Cholinesterase activities as potential biomarkers: characterization in two freshwater snails, Potamopyrgus antipodarum (Mollusca, Hydrobiidae, Smith 1889) and Valvata piscinalis (Mollusca, Valvatidae, Müller 1774)

    OpenAIRE

    Gagnaire, B.; Geffard, O.; Xuereb, B.; Margoum, C.; Garric, J.

    2008-01-01

    Anticholinesterase insecticides constitute a major portion of modern synthetic pesticides and the assessment of cholinesterase (ChE) inhibition is widely used as a specific biomarker for evaluating the exposure of non-target organisms to these pollutants. However, most studies on this biomarker were developed on vertebrates and among invertebrates, gastropod mollusks are rarely used. However, gastropods are important members of aquatic habitats and therefore present a high ecological relevanc...

  15. Plasma cholinesterase inhibition in the clay-colored robin (Turdus grayi) exposed to diazinon in maradol papaya crops in Yucatan, Mexico

    Science.gov (United States)

    Cobos, V.M.; Mora, M.A.; Escalona, G.

    2006-01-01

    The use of organophosphorous pesticides in agriculture can result in intoxication of birds foraging in sprayed crops. Effects on birds resulting from pesticide intoxication are varied and include behavioral and reproductive effects, including death. One widely used insecticide in Maradol papaya crops is diazinon which has been associated with various incidents of intoxication and death of wild birds. The objective of this study was to evaluate the impact of diazinon application to papaya crops on plasma cholinesterase activity of the clay-colored robin (Turdus grayi). We captured clay-colored robins foraging in a papaya crop the following day after the field had been sprayed with diazinon at a dose of 1.5 kg/ha during March and May, respectively. We took a blood sample from the brachialis vein of the birds captured and measured plasma enzymatic activity. The plasma samples from birds used as controls were taken during the same time period and were analyzed in a similar way. Enzymatic activity of males was greater than that of females (53,52%) and mean cholinesterase inhibition was 49.43%. Cholinesterase inhibition was greater during May than in March probably due to more continuous exposure and ingestion of the insecticide through food and possible absorption through the skin. This degree of enzymatic inhibition is possibly affecting the behavior of the clay-colored robin and could result in death in severe cases.

  16. Anti-Cholinesterase Activity of Lycopodium Alkaloids from Vietnamese Huperzia squarrosa (Forst. Trevis

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    Nguyen Ngoc Chuong

    2014-11-01

    Full Text Available A series of Lycopodium alkaloids, namely lycosquarosine A (1, acetylaposerratinine (2, huperzine A (3, huperzine B (4, 8α-hydrophlemariurine B (5, and huperzinine (6, has been isolated from Vietnamese Huperzia squarrosa. Among them, lycosquarosine A (1 is the new metabolite of the natural source. Lycosquarosine A completely inhibited AChE activity in a dose dependent manner with an IC50 value of 54.3 μg/mL, while acetylaposerratinine (2 showed stronger inhibitory activity than 1 with an IC50 value of 15.2 µg/mL. This result indicates that these alkaloids may be a potent source of AChE inhibitors.

  17. Alpha glucosidase inhibitors

    National Research Council Canada - National Science Library

    Kalra, Sanjay

    2014-01-01

    Alpha glucosidase inhibitors (AGIs) are a unique class of anti-diabetic drugs. Derived from bacteria, these oral drugs are enzyme inhibitors which do not have a pancreato -centred mechanism of action...

  18. Proton pump inhibitors

    Science.gov (United States)

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by glands in ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a ...

  19. Antioxidant and Cholinesterase Inhibitory Activities of Ethyl Acetate Extract ofTerminalia chebula: Cell-freeIn vitroandIn silicoStudies.

    Science.gov (United States)

    Rajmohamed, Mohamed Asik; Natarajan, Suganthy; Palanisamy, Premkumar; Abdulkader, Akbarsha Mohammad; Govindaraju, Archunan

    2017-10-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder clinically characterized by memory loss and impaired cognitive function. Cholinergic enzyme deficiency and oxidative stress are the two major factors implicated in the pathogenesis of AD. The symptomatic treatment, as of now, is the use of cholinesterase inhibitors toward cholinergic "downturn." Therefore, there is a search for compounds that will be useful in focused therapies. There has been suggestion that Terminalia chebula fruit would be a potential source. To assess the anticholinesterase and antioxidant activities of T. chebula fruit which is widely practiced in the Ayurvedic medicines for memory enhancement. Ethyl acetate extract of T. chebula fruit (TCEA) was subjected to phytochemical investigation of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities and cell-free antioxidant activity. TCEA was further subjected to gas chromatography-mass spectrum (GC-MS) analysis. The bioactive compounds were analyzed for molecular docking with AChE and BuChE proteins. TCEA exhibited potent AChE and BuChE inhibitory activities comparable to the standard drug donepezil. In vitro cell-free antioxidant assays demonstrated that TCEA possesses excellent free radical scavenging activity, reducing power, and potent metal-chelating activity. Total polyphenolic content of TCEA was 596.75 ± 0.35 µg gallic acid equivalents/mg of extract, which correlates with the antioxidant activity of TCEA. Molecular docking of compounds expounded in GC-MS analysis for AChE and BuChE enzyme activities revealed that methyl N-(N-benzyloxycarbonyl-beta-l-aspartyl)-beta-d-glucosaminide as the most potent compound with good predicted activities. Overall, the results revealed that the bioactive molecule methyl N-(N-benzyloxycarbonyl-beta-l-aspartyl)-beta-d-glucosaminide present in TCEA is a potential depressant for the treatment of AD and related neurodegenerative disorders. The present study was

  20. Acute toxicity and cholinesterase inhibition of the nematicide ethoprophos in larvae of gar Atractosteus tropicus (Semionotiformes: Lepisosteidae).

    Science.gov (United States)

    Mena Torres, Freylan; Pfennig, Sascha; Arias Andrés, María de Jesús; Márquez-Couturier, Gabriel; Sevilla, Adrían; Protti, C Maurizio

    2012-03-01

    Biomarkers are a widely applied approach in environmental studies. Analyses of cholinesterase (ChE), glutathione S-transferase (GST) and lipid peroxidation (LPO) are biomarkers that can provide information regarding early effects of pollutants at different biochemical levels on an organism. The aim of this study was to evaluate the biomarker approach on a Costa Rican native and relevant species. For this, larvae of gar (Atractosteus tropicus) were exposed to the organophosphorus nematicide, ethoprophos. Acute (96hr) exposure was conducted with pesticide concentrations ranging from 0.1 microg/L to 1 500 microg/L. The 96hr LC50 calculated was 859.7 microg/L. After exposure, three biomarkers (ChE, GST and LPO) were analyzed in fish that survived the acute test. The lowest observed effect concentration (LOEC) regarding ChE activity inhibition was 50 microg/L. This concentration produced a significant inhibition (pEthoprophos concentration of 400 microg/L caused a ChE inhibition by 79%. In this study, no significant variations (p>0.05) in GST activity and LPO were observed in A. tropicus larvae after exposure to ethoprophos.

  1. Acute toxicity and cholinesterase inhibition of the nematicide ethoprophos in larvae of gar Atractosteus tropicus (Semionotiformes: Lepisosteidae

    Directory of Open Access Journals (Sweden)

    Freylan Mena Torres

    2012-03-01

    Full Text Available Biomarkers are a widely applied approach in environmental studies. Analyses of cholinesterase (ChE, glutathione S-transferase (GST and lipid peroxidation (LPO are biomarkers that can provide information regarding early effects of pollutants at different biochemical levels on an organism. The aim of this study was to evaluate the biomarker approach on a Costa Rican native and relevant species. For this, larvae of gar (Atractosteus tropicus were exposed to the organophosphorus nematicide, ethoprophos. Acute (96hr exposure was conducted with pesticide concentrations ranging from 0.1μg/L to 1 500μg/L. The 96hr LC50 calculated was 859.7μg/L. After exposure, three biomarkers (ChE, GST and LPO were analyzed in fish that survived the acute test. The lowest observed effect concentration (LOEC regarding ChE activity inhibition was 50μg/L. This concentration produced a significant inhibition (p0.05 in GST activity and LPO were observed in A. tropicus larvae after exposure to ethoprophos.

  2. Evaluation of Citrus aurantifolia peel and leaves extracts for their chemical composition, antioxidant and anti-cholinesterase activities.

    Science.gov (United States)

    Loizzo, Monica Rosa; Tundis, Rosa; Bonesi, Marco; Menichini, Federica; De Luca, Damiano; Colica, Carmela; Menichini, Francesco

    2012-12-01

    The replacement of synthetic antioxidants by safe natural antioxidants fosters research on the screening of vegetables and food as sources of new antioxidants. Moreover, oxidative degeneration of cells is associated with neurodegenerative diseases such as Alzheimer's disease. On the basis of these considerations this work aimed to investigate the antioxidant properties [by using the diphenyl picryl hydrazyl, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and ferric reducing ability of plasma assays, and the β-carotene bleaching test] and the anti-cholinesterase activity of Citrus aurantifolia peel and leaves from different areas of growth. Methanol extracts of the peel and leaves demonstrated the strongest radical scavenging activity. A similar trend was observed with the reducing ability, with values from 112.1 to 146.0 µmol L(-1) Fe(II) g(-1). The relationship between phenol and flavonoid contents and antioxidant activity was statistically investigated. Based on analysis by high-performance liquid chromatography, the most abundant flavonoids found in C. aurantifolia extracts were apigenin, rutin, quercetin, kaempferol and nobiletin. n-Hexane fractions of both peel and leaves showed a good acetylcholinesterase inhibitory activity with IC(50) values in the range 91.4-107.4 µg mL(-1). Gas chromatography-mass spectrometry analysis revealed the presence of monoterpenes and sesquiterpenes as most common components. The findings of this study suggest a potential use of C. aurantifolia peel and leaves for supplements for human health. Copyright © 2012 Society of Chemical Industry.

  3. Serum cholinesterase: a potential assistant biomarker for hand, foot, and mouth disease caused by enterovirus 71 infection.

    Science.gov (United States)

    Cheng, Bang-Ning; Jin, Yu-Lian; Chen, Bi-Quan; Zhu, Li-Yan; Xu, Zi-Cheng; Shen, Tao

    2016-03-29

    Hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) is a potentially life-threatening infectious disease that commonly occurs in children. Diagnosis of HFMD caused by EV71 largely depends on clinical manifestations and rare serological biomarkers used to identify children suffering from HFMD. Serum cholinesterase (SChE) activity has frequently been reported as a potential biomarker for solid central nervous system tumors, chronic heart failure, and liver cirrhosis. However, its potential value in the diagnosis of neurotropic virus infections, such as HFMD caused by EV71, remains to be determined. In our study, 220 children hospitalized with HFMD caused by EV71, 34 inpatients infected with coxsackievirus A16 (CVA16), and 43 undefined enterovirus-infected HFMD inpatients were recruited at the Anhui Provincial Children's Hospital between January 2011 and December 2012. SChE activity was measured. The non-parametric Mann-Whitney U test showed that SChE activity in children diagnosed with HFMD caused by EV71 was significantly higher than in healthy controls (p  0.05). An important finding was that SChE activity declined in the recovery phase of HFMD caused by EV71 compared to the acute phase (p < 0.001). Elevated SChE activity was observed in patients with severe HFMD caused by EV71. Therefore, SChE might be a potential assistant biomarker for the diagnosis of HFMD caused by EV71 in children.

  4. The Glutathione-S-Transferase, Cytochrome P450 and Carboxyl/Cholinesterase Gene Superfamilies in Predatory Mite Metaseiulus occidentalis.

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    Ke Wu

    Full Text Available Pesticide-resistant populations of the predatory mite Metaseiulus (= Typhlodromus or Galendromus occidentalis (Arthropoda: Chelicerata: Acari: Phytoseiidae have been used in the biological control of pest mites such as phytophagous Tetranychus urticae. However, the pesticide resistance mechanisms in M. occidentalis remain largely unknown. In other arthropods, members of the glutathione-S-transferase (GST, cytochrome P450 (CYP and carboxyl/cholinesterase (CCE gene superfamilies are involved in the diverse biological pathways such as the metabolism of xenobiotics (e.g. pesticides in addition to hormonal and chemosensory processes. In the current study, we report the identification and initial characterization of 123 genes in the GST, CYP and CCE superfamilies in the recently sequenced M. occidentalis genome. The gene count represents a reduction of 35% compared to T. urticae. The distribution of genes in the GST and CCE superfamilies in M. occidentalis differs significantly from those of insects and resembles that of T. urticae. Specifically, we report the presence of the Mu class GSTs, and the J' and J" clade CCEs that, within the Arthropoda, appear unique to Acari. Interestingly, the majority of CCEs in the J' and J" clades contain a catalytic triad, suggesting that they are catalytically active. They likely represent two Acari-specific CCE clades that may participate in detoxification of xenobiotics. The current study of genes in these superfamilies provides preliminary insights into the potential molecular components that may be involved in pesticide metabolism as well as hormonal/chemosensory processes in the agriculturally important M. occidentalis.

  5. Inhibition of Cholinesterases and Some Pro-Oxidant induced Oxidative Stress in Rats Brain by Two Tomato (Lycopersicon Esculentum) Varieties

    Science.gov (United States)

    Oboh, G.; Bakare, O.O.; Ademosun, A.O.; Akinyemi, A.J.; Olasehinde, T.A.

    2015-01-01

    This study sought to investigate the effects of two tomato varieties [Lycopersicon esculentum Mill. var. esculentum (ESC) and Lycopersicon esculentum Mill. var. cerasiforme (CER)] on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities in vitro. Phenolics content, carotenoids characterisation, inhibition of Fe2+ and quinolinic acid-induced malondialdehyde (MDA) production in rats brain homogenate and NO* scavenging abilities were also assesed in addition to the AChE and BChE inhibition assays. There was no significant difference in the AChE inhibitory ability of the samples, while CER had significantly higher BChE inhibitory activity. Furthermore, the tomatoes inhibited Fe2+ and quinolinic acid-induced MDA production and further exhibited antioxidant activities through their NO* scavenging abilities. There was no significant difference in the phenolic content of the samples, while significantly high amounts of lycopene were detected in the tomatoes. The cholinesterase-inhibition and antioxidant properties of the “tomatoes” could make them good dietary means for the management of neurodegenerative disorders.

  6. In vitro exposure of heavy metals on nucleotidase and cholinesterase activities from the digestive gland of Helix aspersa.

    Science.gov (United States)

    de Souza Dahm, Kelly Cristine; Rückert, Caroline; Tonial, Elisa Marchezan; Bonan, Carla Denise

    2006-07-01

    Zinc, copper and cadmium are important environmental contaminants and differences in purinergic and cholinergic systems of invertebrates have been described when compared to characteristics of these signaling systems in vertebrates. Here we evaluate the effect in vitro of these metals on the ATPase, 5'-nucleotidase and cholinesterase (ChE) activities in the digestive gland of Helix aspersa. Zinc (500 and 1000 microM) promoted a significant decrease in 5'-nucleotidase activity. However, it did not induce changes in ATP hydrolysis. Copper (25 and 50 microM), inhibited significantly ATPase activity, but did not alter 5'-nucleotidase when compared to control (no metal added). In relation to effects of cadmium, an inhibitory effect on ATP hydrolysis has been observed at concentrations of 100, 500 and 1000 microM and a similar decrease of AMP hydrolysis was observed at 500 and 1000 microM. However, there were no significant changes in ChE activity from homogenates of the digestive gland of H. aspersa for all metals tested. This study demonstrated that zinc, cadmium and copper affect ATPase and 5'-nucleotidase in digestive gland, but not ChE, suggesting that the purinergic system may be a target related to toxicity induced by these metals and a possible indicator of biological impact of exposure to these contaminants.

  7. The Use of Selected Biomarkers, Phagocytic and Cholinesterase Activity to Detect the Effects of Dimethoate on Marine Mussel (Mytilus edulis

    Directory of Open Access Journals (Sweden)

    KHUSNUL YAQIN

    2008-03-01

    Full Text Available Effects of organophosphorous pesticide, dimethoate on blue mussels, Mytilus edulis using selected biomarkers have been studied. Mussels were exposed to serial dilutions of dimethoate, 7.88, 15.75, 31.35, and 63.00 µg/l including positive and negative controls for 14 days. The suppression effects of dimethoate on phagocytic activity significantly occurred at two lowest concentrations of dimethoate (7.88 and 15.75 µg/l, but stimulation effects significantly emerged at the following highest concentrations (31.35 and 63.00 µg/l. The declining tendency of the cholinesterase (ChE activity (23% lower than the control appeared when mussels exposed to 7.88 and 15.75 µg/l dimethoate. Moreover, the significant inhibition of the ChE activity occurred at 31.35 µg/l dimethoate exposure. This study suggested that the phagocytic and the ChE activity are useful biomarkers for assessing the affects of organophosporous pesticide, dimethoate on neuro-immune system of blue mussels, M. edulis.

  8. Chemical Composition of Volatiles; Antimicrobial, Antioxidant and Cholinesterase Inhibitory Activity of Chaerophyllum aromaticum L. (Apiaceae) Essential Oils and Extracts.

    Science.gov (United States)

    Petrović, Goran M; Stamenković, Jelena G; Kostevski, Ivana R; Stojanović, Gordana S; Mitić, Violeta D; Zlatković, Bojan K

    2017-05-01

    The present study reports the chemical composition of the headspace volatiles (HS) and essential oils obtained from fresh Chaerophyllum aromaticum root and aerial parts in full vegetative phase, as well as biological activities of their essential oils and MeOH extracts. In HS samples, the most dominant components were monoterpene hydrocarbons. On the other hand, the essential oils consisted mainly of sesquiterpenoids, representing 73.4% of the root and 63.4% of the aerial parts essential oil. The results of antibacterial assay showed that the aerial parts essential oil and MeOH extract have no antibacterial activity, while the root essential oil and extract showed some activity. Both of the tested essential oils exhibited anticholinesterase activity (47.65% and 50.88%, respectively); MeOH extract of the root showed only 8.40% inhibition, while aerial part extract acted as an activator of cholinesterase. Regarding the antioxidant activity, extracts were found to be more effective than the essential oils. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

  9. Thermostabilisation of human serum butyrylcholinesterase for detection of its inhibitors in water and biological fluids

    Directory of Open Access Journals (Sweden)

    Lakshmanan Jaganathan

    1999-01-01

    Full Text Available The ability of gelatine-trehalose to convert the normally fragile, dry human serum BChE into a thermostable enzyme and its use in the detection of cholinesterase inhibitors in water and biological fluids is described. Gelatine or trehalose alone is unable to protect the dry enzyme against exposure to high temperature, while a combination of gelatine and trehalose were able to protect the enzyme activity against prolonged exposure to temperature as high as +50°C. A method for rapid, simple and inexpensive means of screening for cholinesterase inhibitors such as carbamates and organophosphates in water, vegetables and human blood has been developed.A capacidade da gelatina-trehalose em converter a frágil BChE do soro humano em uma enzima termoestável e seu uso na descoberta de inibidores de colinesterase em água e fluidos biológicos é apresentado. A Gelatina ou trehalose são incapazes de proteger a enzima seca BchE do soro humano contra exposição a elevadas temperaturas, enquanto que uma combinação de gelatina e trehalose são capazes de proteger a atividade de enzima contra exposição prolongada a temperaturas elevadas e da ordem de 50° C. Um método barato, simples e rápido de screening para inibidores de colinesterase tal como carbamatos e organofosfatos em água, verduras e sangue humano foi desenvolvido.

  10. Clinical meaningfulness of Alzheimer's Disease Assessment Scale-Cognitive subscale change in relation to goal attainment in patients on cholinesterase inhibitors.

    Science.gov (United States)

    Rockwood, Kenneth; Howlett, Susan E; Hoffman, Deborah; Schindler, Rachel; Mitnitski, Arnold

    2017-10-01

    The clinical meaningfulness of Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) subscale change is disputed. We compared 2- to 4-point ADAS-Cog changes with changes in Goal Attainment Scaling (GAS) and everyday function across initial ADAS-Cog scores and treatment responses. This exploratory analysis evaluated mild-moderate Alzheimer's disease patients treated with donepezil (12 months) or galantamine (8 months). Clinical meaningfulness was defined as concomitant ADAS-Cog and GAS changes of ±3 points and/or functional improvement. Patients with ≥3-point ADAS-Cog improvement significantly improved on GAS but not on standard tests of everyday function. ADAS-Cog "no change" (≤±3 points) was seen with mean GAS improvement. Initial ADAS-Cog improvement made endpoint improvement (ADAS-Cog 3 points and GAS 1 point) more likely (odds ratio = 6.9; 95% confidence interval = 2.5-19.5). In contrast, initial deterioration made endpoint improvement unlikely (0.33; 0.14-0.64). ADAS-Cog improvement and no change were each associated with GAS improvement. Initial ADAS-Cog worsening was unlikely to result in later improvement. ISRCTN26167328. Copyright © 2017. Published by Elsevier Inc.

  11. Effects of organophosphates on cholinesterase activity and neurite regeneration in Aplysia.

    Science.gov (United States)

    Srivatsan, M

    1999-05-14

    In Aplysia, a marine mollusc, acetylcholinesterase (AChE) is present in cholinergic and non-cholinergic neurons and in hemolymph. Aplysia hemolymph has a very high level of AChE which promotes neurite growth in primary cultures of dopaminergic neurons via a non-catalytic mechanism. In contrast, AChE is known to facilitate neurite growth in cholinoceptive neurons by hydrolyzing ACh which inhibits neurite growth. In order to test whether AChE's site-specific neurotrophic action varies with the neuronal phenotype, we investigated the effects of active-site inhibited hemolymph AChE on neurite growth of cholinergic neurons of Aplysia in primary culture. Organophosphates being long-acting active site inhibitors of AChE were chosen for this study. The effects of active site inhibited hemolymph AChE was tested on large cholinergic neurons, R2 (abdominal ganglion) and LPL1 (left pleural ganglion) as well as small cholinergic neurons (buccal ganglion) of Aplysia, maintained in culture. Partially purified hemolymph AChE was inhibited by either 10 microM of echothiophate or 5 microM of paraoxon. Neurons were maintained in (1) L15 (defined medium) alone; (2) L15 + echothiophate; (3) L-15 + paraoxon; (4) L-15 + hemolymph AChE; (5) L15 + hemolymph AChE + echothiophate; and (6) L-15 + hemolymph AChE + paraoxon. Addition of uninhibited hemolymph AChE significantly increased neurite growth of cultured neurons compared to L15 alone. In the presence of echothiophate-inhibited or praoxon-inhibited AChE, neurite growth was significantly reduced when compared to L15 + uninhibited AChE. While the presence of echothiophate by itself did not reduce survival or neurite growth when compared to L-15 alone, the presence of paraoxon by itself markedly reduced survival and neurite growth of cultured neurons. The results show that AChE's catalytic action contributes to enhance neurite growth in cholinergic neurons and the effects of paraoxon appears to differ from that of echothiophate on

  12. Annual Check-up

    Science.gov (United States)

    ... Medical Conditions Nutrition & Fitness Emotional Health Annual Check-Up Posted under Health Guides . Updated 24 April 2017. + ... I get ready for my annual medical check-up? If this is your first visit to your ...

  13. Integrated Lateral Flow Test Strip with Electrochemical Sensor for Quantification of Phosphorylated Cholinesterase: Biomarker of Exposure to Organophosphorus Agents

    Energy Technology Data Exchange (ETDEWEB)

    Du, Dan; Wang, Jun; Wang, Limin; Lu, Donglai; Lin, Yuehe

    2012-02-08

    An integrated lateral flow test strip with electrochemical sensor (LFTSES) device with rapid, selective and sensitive response for quantification of exposure to organophosphorus (OP) pesticides and nerve agents has been developed. The principle of this approach is based on parallel measurements of post-exposure and baseline acetylcholinesterase (AChE) enzyme activity, where reactivation of the phosphorylated AChE is exploited to enable measurement of total amount of AChE (including inhibited and active) which is used as a baseline for calculation of AChE inhibition. Quantitative measurement of phosphorylated adduct (OP-AChE) was realized by subtracting the active AChE from the total amount of AChE. The proposed LFTSES device integrates immunochromatographic test strip technology with electrochemical measurement using a disposable screen printed electrode which is located under the test zone. It shows linear response between AChE enzyme activity and enzyme concentration from 0.05 to 10 nM, with detection limit of 0.02 nM. Based on this reactivation approach, the LFTSES device has been successfully applied for in vitro red blood cells inhibition studies using chlorpyrifos oxon as a model OP agent. This approach not only eliminates the difficulty in screening of low-dose OP exposure because of individual variation of normal AChE values, but also avoids the problem in overlapping substrate specificity with cholinesterases and avoids potential interference from other electroactive species in biological samples. It is baseline free and thus provides a rapid, sensitive, selective and inexpensive tool for in-field and point-of-care assessment of exposures to OP pesticides and nerve agents.

  14. Aqueous extracts of avocado pear (Persea americana Mill.) leaves and seeds exhibit anti-cholinesterases and antioxidant activities in vitro.

    Science.gov (United States)

    Oboh, Ganiyu; Odubanjo, Veronica O; Bello, Fatai; Ademosun, Ayokunle O; Oyeleye, Sunday I; Nwanna, Emem E; Ademiluyi, Adedayo O

    2016-03-01

    Avocado pear (Persea americana Mill.) leaves and seeds are used in traditional medicine for the treatment/management of Alzheimer disease (AD); however, information on the mechanism of actions is limited. This study sought to investigate the effect of P. americana leaf and seed aqueous extracts on some enzymes linked with AD (acetylcholinesterase [AChE] and butyrylcholinesterase [BChE] activities) and their antioxidant potentials in vitro. The inhibitory effects of extracts on AChE and BChE activities and antioxidant potentials (inhibition of Fe2+- and sodium nitroprusside-induced thiobarbiturate reactive species [TBARS] production in rat brain homogenates, radicals [1,1-diphenyl-2-picrylhydrazyl, hydroxyl, and nitric oxide] scavenging and iron [Fe] chelation abilities) were investigated. Phenolic content and phytochemical screening were carried out. Alkaloid profile was also determined using gas chromatography coupled with flame ionization detector (GC-FID). The extracts inhibited AChE and BChE activities and prooxidant-induced TBARS production in a dose-dependent manner, with the seed extract having the highest inhibitory effect and the leaf extract exhibiting higher phenolic content and radical scavenging abilities, but lower Fe chelation ability compared with that of the seed. The phytochemical screening revealed the presence of saponins, alkaloids, and terpenoids in both extracts, whereas the total alkaloid profile was higher in the seed extract than in the leaf extract, as revealed by GC-FID. The anti-cholinesterase and antioxidant activities of avocado leaf and seed could be linked to their phytoconstituents and might be the possible mechanisms underlying their use as a cheap and natural treatment/management of AD. However, these extracts should be further investigated in vivo.

  15. Organophosphate Insecticides Target the Serotonergic System in Developing Rat Brain Regions: Disparate Effects of Diazinon and Parathion at Doses Spanning the Threshold for Cholinesterase Inhibition

    OpenAIRE

    Slotkin, Theodore A.; Tate, Charlotte A.; Ryde, Ian T.; Levin, Edward D.; Seidler, Frederic J.

    2006-01-01

    Background In the developing brain, serotonin (5HT) systems are among the most sensitive to disruption by organophosphates. Objectives We exposed neonatal rats to daily doses of diazinon or parathion on postnatal days (PND)1–4 and evaluated 5HT receptors and the 5HT transporter in brainstem and forebrain on PND5, focusing on doses of each agent below the maximum tolerated dose and spanning the threshold for cholinesterase inhibition: 0.5, 1, or 2 mg/kg for diazinon, and 0.02, 0.05, and 0.1 mg...

  16. State-wide hospital clinical laboratory plan for measuring cholinesterase activity for individuals suspected of exposure to nerve agent chemical weapons.

    Science.gov (United States)

    Wu, Alan H B; Smith, Andrew; McComb, Robert; Bowers, George N; Makowski, Gregory S; McKay, Charles A; Vena, Jason; McDonagh, John; Hopfer, Sidney; Sena, Salvatore F; Malkus, Herbert; Forte, Elaine; Kelly, Katherine

    2008-02-01

    Hospital laboratories currently lack the capacity to provide emergency determination of cholinesterase activity. We have developed a hospital-based 3-tiered system to test plasma for butyrylcholinesterase (BChE) activity and whole blood for red cell acetylcholinesterase (AChE) activity using available technology and personnel. Interagency communications, toxidrome definition, and patient triage will be coordinated by the Connecticut Department of Public Health and the Poison Control Center. Initial BChE data documents good precision between institutions (coefficient of variation chemical terrorism or large scale HazMat events.

  17. DPP-4 inhibitors

    DEFF Research Database (Denmark)

    Deacon, Carolyn F.

    2016-01-01

    Dipeptidyl peptidase (DPP)-4 inhibitors inhibit the activity of the enzyme responsible for the initial rapid degradation of the incretin hormones, thereby enhancing their antihyperglycemic effects.......Dipeptidyl peptidase (DPP)-4 inhibitors inhibit the activity of the enzyme responsible for the initial rapid degradation of the incretin hormones, thereby enhancing their antihyperglycemic effects....

  18. Estimation of cholinesterase inhibitory and antioxidant effects of the leaf extracts of Anatolian Ficus carica var. domestica and their total phenol and flavonoid contents.

    Science.gov (United States)

    Orhan, Ilkay Erdogan; Ustün, Osman; Sener, Bilge

    2011-03-01

    Ficus carica var. domestica Tsch. & Rav. (common fig) is widely grown in Turkey and exported for its edible fruits. In this study, the n-hexane, chloroform, acetone, methanol, n-butanol, and water extracts of the leaves of F. carica var. domestica were screened for their cholinesterase inhibitory and antioxidant activities. Cholinesterase inhibition against acetyl- (AChE) and butyrylcholinesterase (BChE) was measured by the spectrophotometric method of Ellman at concentrations of 25, 50, and 100 microg/mL., while antioxidant activity was tested using three in vitro methods; 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, metal-chelation capacity, and ferric-reducing antioxidant power (FRAP). Total phenol and flavonoid contents of the extracts were determined spectrophotometrically. Our results revealed that the n-hexane and acetone extracts exerted a notable inhibition against both AChE (62.9 +/- 0.9% and 50.8 +/- 2.1%, respectively) and BChE (76.9 +/- 2.2% and 45.6 +/- 1.3%, respectively). However, they had low activity in the antioxidant tests. The chloroform extract was found to be the richest in total flavonoid content (252.5 +/- 1.1 mg/g quercetin equivalent), while the n-butanol extract had the highest total phenol amount (85.9 +/- 3.2 mg/g extract gallic acid equivalent).

  19. Acute toxicity and cholinesterase inhibition of the nematicide ethoprophos in larvae of gar Atractosteus tropicus (Semionotiformes: Lepisosteidae

    Directory of Open Access Journals (Sweden)

    Freylan Mena Torres

    2012-03-01

    Full Text Available Biomarkers are a widely applied approach in environmental studies. Analyses of cholinesterase (ChE, glutathione S-transferase (GST and lipid peroxidation (LPO are biomarkers that can provide information regarding early effects of pollutants at different biochemical levels on an organism. The aim of this study was to evaluate the biomarker approach on a Costa Rican native and relevant species. For this, larvae of gar (Atractosteus tropicus were exposed to the organophosphorus nematicide, ethoprophos. Acute (96hr exposure was conducted with pesticide concentrations ranging from 0.1μg/L to 1 500μg/L. The 96hr LC50 calculated was 859.7μg/L. After exposure, three biomarkers (ChE, GST and LPO were analyzed in fish that survived the acute test. The lowest observed effect concentration (LOEC regarding ChE activity inhibition was 50μg/L. This concentration produced a significant inhibition (p0.05 in GST activity and LPO were observed in A. tropicus larvae after exposure to ethoprophos.El proceso de reproducción inducida de Atractosteus tropicus es útil para la acuicultura y la reintroducción en zonas donde las poblaciones silvestres se han reducido considerablemente. En larvas de esta especie se evaluó la toxicidad aguda, así como la respuesta de tres biomarcadores: actividad colinesterasa (ChE, actividad de Glutation S-transferasa (GST y peroxidación de lípidos (LPO. Asimismo, se realizaron exposiciones agudas (96hr a etoprofos (nematicida organofosforado, en donde se utilizaron concentraciones entre 0.1μg/L y 1 500μg/L del nematicida. La concentración letal 50 (LC50 calculada fue de 859.7μg/L; la máxima concentración sin efecto en los organismos (NOEC 10μg/L y la concentración más baja en la cual se observó algún efecto (LOEC 50μg/L. A esa concentración, el efecto observado fue una reducción significativa (p0.05 luego de la exposición de los organismos a etoprofos.

  20. Time course of cholinesterase inhibition in adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl or propoxur.

    Science.gov (United States)

    Padilla, S; Marshall, R S; Hunter, D L; Lowit, A

    2007-03-01

    To compare the toxicity of seven N-methyl carbamates, time course profiles for brain and red blood cell (RBC) cholinesterase (ChE) inhibition were established for each. Adult, male, Long Evans rats (n=4-5 dose group) were dosed orally with either carbaryl (30 mg/kg in corn oil); carbofuran (0.5 mg/kg in corn oil); formetanate HCl (10 mg/kg in water); methomyl (3 mg/kg in water); methiocarb (25 mg/kg in corn oil); oxamyl (1 mg/kg in water); or propoxur (20 mg/kg in corn oil). This level of dosing produced at least 40% brain ChE inhibition. Brain and blood were taken from 0.5 to 24 h after dosing for analysis of ChE activity using two different methods: (1) a radiometric method which limits the amount of reactivation of ChE activity, and (2) a spectrophotometric method (Ellman method using traditional, unmodified conditions) which may encourage reactivation. The time of peak ChE inhibition was similar for all seven N-methyl carbamate pesticides: 0.5-1.0 h after dosing. By 24 h, brain and RBC ChE activity in all animals returned to normal. The spectrophotometric method underestimated ChE inhibition. Moreover, there was a strong, direct correlation between brain and RBC ChE activity (radiometric assay) for all seven compounds combined (r(2)=0.73, slope 1.1), while the spectrophotometric analysis of the same samples showed a poor correlation (r(2)=0.09). For formetanate, propoxur, methomyl, and methiocarb, brain and RBC ChE inhibitions were not different over time, but for carbaryl, carbofuran and oxamyl, the RBC ChE was slightly more inhibited than brain ChE. These data indicate (1) the radiometric method is superior for analyses of ChE activity in tissues from carbamate-treated animals (2) that animals treated with these N-methyl carbamate pesticides are affected rapidly, and recover rapidly, and (3) generally, assessment of RBC ChE is an accurate predictor of brain ChE inhibition for these seven pesticides.

  1. Developing antibodies from cholinesterase derived from prokaryotic expression and testing their feasibility for detecting immunogen content in Daphnia magna *

    Science.gov (United States)

    Liu, Hong-cui; Yuan, Bing-qiang; Li, Shao-nan

    2016-01-01

    To yield cholinesterase (ChE) from prokaryotic expression, the ChE gene that belongs to Daphnia magna was amplified by reverse transcription-polymerase chain reaction (RT-PCR) using forward primer 5'-CCCYGGNGCSAT GATGTG-3' and reverse primer 5'-GYAAGTTRGCCCAATATCT-3'. To express the gene, one sequence of the amplified DNA, which was able to encode a putative protein containing two conserved carboxylesterase domains, was connected to the prokaryotic expression vector PET-29a(+). The recombinant vector was transformed into Escherichia coil BL21 (DE3). Protein expression was induced by isopropy-D-thiogalactoside. The expressed ChE was used as an immunogen to immunize BALB/c mice. The obtained antibodies were tested for their specificity towards crude enzymes from species such as Alona milleri, Macrobrachium nipponense, Bombyx mori, Chironomus kiiensis, Apis mellifera, Eisenia foetida, Brachydanio rerio, and Xenopus laevis. Results indicated that the antibodies had specificity suitable for detecting ChE in Daphnia magna. A type of indirect and non-competitive enzyme-linked immunosorbent assay (IN-ELISA) was used to test the immunoreactive content of ChE (ChE-IR) in Daphina magna. The detection limit of the IN-ELISA was found to be 14.5 ng/ml at an antiserum dilution of 1:22 000. Results from tests on Daphnia magna exposed to sublethal concentrations of triazophos indicated a maximal induction of 57.2% in terms of ChE-IR on the second day after the animals were exposed to a concentration of 2.10 μg/L triazophos. Testing on animals acclimatized to a temperature of 16 °C indicated that ChE-IR was induced by 16.9% compared with the ChE-IR content detected at 21 °C, and the rate of induction was 25.6% at 10 °C. The IN-ELISA was also used to test the stability of ChE-IR in collected samples. Repeated freezing and thawing had no influence on the outcome of the test. All these results suggest that the polyclonal antibodies developed against the recombinant ChE are as

  2. Developmental abnormalities and changes in cholinesterase activity in sea urchin embryos and larvae from sperm exposed to engineered nanoparticles.

    Science.gov (United States)

    Gambardella, Chiara; Aluigi, Maria G; Ferrando, Sara; Gallus, Lorenzo; Ramoino, Paola; Gatti, Antonietta M; Rottigni, Marino; Falugi, Carla

    2013-04-15

    The objective of this study is to examine the toxicity of engineered nanoparticles (NPs) that are dispersed in sea water by using an in vivo model. Because many products of nanotechnology contain NPs and are commonly used and well-established in the market, the accidental release of NPs into the air and water is quite possible. Indeed, at the end of their life cycle, some NPs are inevitably released into waste water and can reach marine ecosystem and affect the organisms there. Although there are few data on the presence of NPs in the marine environment, our awareness of their potential impact on environmental and organismal health is growing. Shallow-water benthonic organisms such as sea urchins provide planktonic larvae as a trophic base for finfish juveniles and are exposed to water from estuaries and precipitation. Such organisms can therefore be directly affected by NPs that are dispersed into those media. We evaluated the effects of exposure to different concentrations of nanosilver, titanium oxide and cobalt NPs on the sperm of the sea urchin Paracentrotus lividus by analyzing the functionality and the morphology and biochemistry of the first developmental stages of the sea urchin. Sperm were exposed to sea water containing suspensions of NPs ranging from 0.0001 mg/L to 1 mg/L. Fertilization ability was not affected, but developmental anomalies were identified in embryos from the gastrula to pluteus stages, including morphological alterations of the skeletal rods. In addition, the enzymatic activity (cholinesterase, ChE) of the larvae was measured. Acetylcholinesterase (AChE) and propionylcholinesterase activity (PrChE) was affected in all of the exposed samples. The results did not vary consistently with the concentration of NP, but controls were significantly different from exposed samples. Exposure of sea urchin to these NPs may cause neurotoxic damage, and the altered ChE activity may be involved in skeletogenic aberrations. In conclusion, the sea urchin

  3. Annual Statistical Supplement, 2002

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2002 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  4. Annual Statistical Supplement, 2003

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2003 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  5. Annual Statistical Supplement, 2001

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2001 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  6. Annual Statistical Supplement, 2010

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2010 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  7. Annual Statistical Supplement, 2007

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2007 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  8. Annual Statistical Supplement, 2016

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2016 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  9. Annual Statistical Supplement, 2000

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2000 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  10. Annual Statistical Supplement, 2008

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2008 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  11. Annual Statistical Supplement, 2006

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2006 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  12. Annual Statistical Supplement, 2005

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2005 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  13. Annual Statistical Supplement, 2015

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2015 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  14. Annual Statistical Supplement, 2004

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2004 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  15. Annual Statistical Supplement, 2014

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2014 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  16. Annual Statistical Supplement, 2009

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2009 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  17. Annual Statistical Supplement, 2011

    Data.gov (United States)

    Social Security Administration — The Annual Statistical Supplement, 2011 includes the most comprehensive data available on the Social Security and Supplemental Security Income programs. More than...

  18. CSIR Annual report 1978

    CSIR Research Space (South Africa)

    CSIR

    1978-01-01

    Full Text Available stream_source_info Annual Report_1978.pdf.txt stream_content_type text/plain stream_size 78 Content-Encoding ISO-8859-1 stream_name Annual Report_1978.pdf.txt Content-Type text/plain; charset=ISO-8859-1 ...

  19. Annual Energy Review, 2008

    Energy Technology Data Exchange (ETDEWEB)

    None

    2009-06-01

    The Annual Energy Review (AER) is the Energy Information Administration's (EIA) primary report of annual historical energy statistics. For many series, data begin with the year 1949. Included are statistics on total energy production, consumption, trade, and energy prices; overviews of petroleum, natural gas, coal, electricity, nuclear energy, renewable energy, and international energy; financial and environment indicators; and data unit conversions.

  20. CSIR Annual report 1972

    CSIR Research Space (South Africa)

    CSIR

    1972-01-01

    Full Text Available stream_source_info Annual Report_ 1972.pdf.txt stream_content_type text/plain stream_size 95 Content-Encoding ISO-8859-1 stream_name Annual Report_ 1972.pdf.txt Content-Type text/plain; charset=ISO-8859-1 ...

  1. 55th Annual

    Indian Academy of Sciences (India)

    1990-01-01

    Jan 1, 1990 ... At the invitation of the Madhya Pradesh. Council of Science and Technology, the. Barkatullah University and the Regional. Research laboratory, Bhopal, the 55th Annual. Meeting of the Academy was held at the. Tagore Bhawan, Bhopal from 10 to 13. November 1989. One of the best organized Annual.

  2. Annual Report 1997

    Energy Technology Data Exchange (ETDEWEB)

    Golnik, N.; Mika, J.R.; Wieteska, K. [eds.

    1998-12-31

    This Annual Report of the Institute of Atomic Energy describes the results of the research works carried out at the Institute at 1997. As in the preceding years the authors of the individual scientific reports published in this Annual Report are fully responsible for their content and layout. The Report contains the information on other activities of the Institute as well. (author)

  3. Multiple Ligands Targeting Cholinesterases and β-Amyloid: Synthesis, Biological Evaluation of Heterodimeric Compounds with Benzylamine Pharmacophore.

    Science.gov (United States)

    Szałaj, Natalia; Bajda, Marek; Dudek, Katarzyna; Brus, Boris; Gobec, Stanislav; Malawska, Barbara

    2015-08-01

    Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N-benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin-1-one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC50  = 33 nM) and beta amyloid aggregation inhibitor. It acts as a non-competitive acetylcholinesterase inhibitor and is able to cross the blood-brain barrier in vitro. We believe that compound 8b represents an important lead compound for further development as potential anti-AD agent. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Acetylcholinesterase enzyme inhibitor activity of some novel pyrazinamide condensed 1,2,3,4-tetrahydropyrimidines

    Directory of Open Access Journals (Sweden)

    Karthikeyan Elumalai

    2015-03-01

    Full Text Available A new series of some novel pyrazinamide condensed 1,2,3,4-tetrahydropyrimidines was prepared by reacting of N-(3-oxobutanoylpyrazine-2-carboxamide with urea/thiourea and appropriate aldehyde in the presence of catalytic amount of laboratory made p-toluenesulfonic acid as an efficient catalyst. Confirmation of the chemical structure of the synthesized compounds (4a–l was substantiated by TLC, different spectral data IR, 1H NMR, mass spectra and elemental analysis. The synthesized compounds were evaluated for acetyl and butyl cholinesterase (AChE and BuChE inhibitor activity. The titled compounds exhibited weak, moderate or high AChE and BuChE inhibitor activity. Especially, compound (4l showed the best AChE and BuChE inhibitory activity of all the 1,2,3,4-tetrahydropyrimidine derivatives, with an IC50 value of 0.11 μM and 3.4 μM.

  5. Interactions of butane, but-2-ene or xylene-like linked bispyridinium para-aldoximes with native and tabun-inhibited human cholinesterases.

    Science.gov (United States)

    Calić, Maja; Bosak, Anita; Kuca, Kamil; Kovarik, Zrinka

    2008-09-25

    Kinetic parameters were evaluated for inhibition of native and reactivation of tabun-inhibited human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7) and human plasma butyrylcholinesterase (BChE, EC 3.1.1.8) by three bispyridinium para-aldoximes with butane (K074), but-2-ene (K075) or xylene-like linker (K114). Tested aldoximes reversibly inhibited both cholinesterases with the preference for binding to the native AChE. Both cholinesterases showed the highest affinity for K114 (K(i) was 0.01 mM for AChE and 0.06 mM for BChE). The reactivation of tabun-inhibited AChE was efficient by K074 and K075. Their overall reactivation rate constants were around 2000 min(-1)M(-1), which is seven times higher than for the classical bispyridinium para-aldoxime TMB-4. The reactivation of tabun-inhibited AChE assisted by K114 was slow and reached 90% after 20 h. Since the aldoxime binding affinity of tabun-inhibited AChE was similar for all tested aldoximes (and corresponded to their K(i)), the rate of the nucleophilic displacement of the phosphoryl-moiety from the active site serine was the limiting factor for AChE reactivation. On the other hand, none of the aldoximes displayed a significant reactivation of tabun-inhibited BChE. Even after 20 h, the reactivation maximum was 60% for 1 mM K074 and K075, and only 20% for 1 mM K114. However, lower BChE affinities for K074 and K075 compared to AChE suggest that the fast tabun-inhibited AChE reactivation by these compounds would not be obstructed by their interactions with BChE in vivo.

  6. Antiaggregation Potential of Padina gymnospora against the Toxic Alzheimer's Beta-Amyloid Peptide 25-35 and Cholinesterase Inhibitory Property of Its Bioactive Compounds.

    Directory of Open Access Journals (Sweden)

    Balakrishnan Shanmuganathan

    Full Text Available Inhibition of β-amyloid (Aβ aggregation in the cerebral cortex of the brain is a promising therapeutic and defensive strategy in identification of disease modifying agents for Alzheimer's disease (AD. Since natural products are considered as the current alternative trend for the discovery of AD drugs, the present study aims at the evaluation of anti-amyloidogenic potential of the marine seaweed Padina gymnospora. Prevention of aggregation and disaggregation of the mature fibril formation of Aβ 25-35 by acetone extracts of P. gymnospora (ACTPG was evaluated in two phases by Thioflavin T assay. The results were further confirmed by confocal laser scanning microscopy (CLSM analysis and Fourier transform infrared (FTIR spectroscopic analysis. The results of antiaggregation and disaggregation assay showed that the increase in fluorescence intensity of aggregated Aβ and the co-treatment of ACTPG (250 μg/ml with Aβ 25-35, an extensive decrease in the fluorescence intensity was observed in both phases, which suggests that ACTPG prevents the oligomers formation and disaggregation of mature fibrils. In addition, ACTPG was subjected to column chromatography and the bioactivity was screened based on the cholinesterase inhibitory activity. Finally, the active fraction was subjected to LC-MS/MS analysis for the identification of bioactive compounds. Overall, the results suggest that the bioactive compound alpha bisabolol present in the alga might be responsible for the observed cholinesterase inhibition with the IC50 value < 10 μg/ml for both AChE and BuChE when compared to standard drug donepezil (IC50 value < 6 μg/ml and support its use for the treatment of neurological disorders.

  7. Vanda roxburghii chloroform extract as a potential source of polyphenols with antioxidant and cholinesterase inhibitory activities: identification of a strong phenolic antioxidant.

    Science.gov (United States)

    Uddin, Md Nasim; Afrin, Rejina; Uddin, Md Josim; Uddin, Md Jalal; Alam, A H M K; Rahman, Aziz Abdur; Sadik, Golam

    2015-06-23

    Alzheimer's disease (AD) is a progressively developing neurodegenerative disorder of the brain in the elderly people. Vanda roxburghii Rbr. root has been used traditionally in Bangladesh as tonic to brain and in the treatment of nervous system disorders including AD. Therefore, we aimed to investigate the cholinesterase inhibitory activities and antioxidant properties of the extracts from V. roxburghii. The crude methanol extract from the roots of plant was sequentially fractionated with petroleum ether, chloroform, ethylacetate and water to yield their corresponding extracts. The extracts were assessed for acetylcholinesterase and butyrylcholinesterase inhibitory activity by modified Ellman method and antioxidant property by several assays including ferric reducing antioxidant power, scavenging of 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical and hydroxyl radical, and inhibition of lipid peroxidation. Endogenous substances in the extracts were analyzed by the standard phytochemical methods and active compound was isolated by the chromatographic methods. Chloroform extract was shown to demonstrate strong ferric-reducing antioxidant power and scavenging activity against DPPH and hydroxyl free radicals when compared with the other extracts and the reference standard catechin. The antioxidant effect was further verified by inhibition of lipid peroxidation in rat brain homogenates. Likewise, the chloroform extract exhibited the highest inhibition against both the acetylcholinesterase and butyrylcholinesterase enzymes with IC50 values of 221.13 and 82.51 μg/ml, respectively. Phytochemical screening revealed a large amount of phenolics and flavonoids in the chloroform extract. Bioactivity guided separation techniques led to the isolation of a strong antioxidant from the chloroform extract and its structure was determined as gigantol on the basis of spectral studies. These results suggest that the chloroform extract of V. roxburghii, possibly due to its phenolic

  8. [Acquired coagulant factor inhibitors].

    Science.gov (United States)

    Nogami, Keiji

    2015-02-01

    Acquired coagulation factor inhibitors are an autoimmune disease causing bleeding symptoms due to decreases in the corresponding factor (s) which result from the appearance of autoantibodies against coagulation factors (inhibitor). This disease is quite different from congenital coagulation factor deficiencies based on genetic abnormalities. In recent years, cases with this disease have been increasing, and most have anti-factor VIII autoantibodies. The breakdown of the immune control mechanism is speculated to cause this disease since it is common in the elderly, but the pathology and pathogenesis are presently unclear. We herein describe the pathology and pathogenesis of factor VIII and factor V inhibitors. Characterization of these inhibitors leads to further analysis of the coagulation process and the activation mechanisms of clotting factors. In the future, with the development of new clotting examination method (s), we anticipate that further novel findings will be obtained in this field through inhibitor analysis. In addition, detailed elucidation of the coagulation inhibitory mechanism possibly leading to hemostatic treatment strategies for acquired coagulation factor disorders will be developed.

  9. Annual Report to Congress

    Science.gov (United States)

    2008-05-01

    Lipid synthesis inhibitors 2007 n GSK Gyrase inhibitors 2007 n Implicit Immunomodulator dipeptide 2007 n USAMRIID Licensed FQ, immunomodulators 2007...currently fielded Convulsant Antidote Nerve Agent (CANA) that uses diazepam . Midazolam is more water-soluble than diazepam (for quicker absorption into...the blood stream). In animal models, midazolam terminates nerve agent-induced seizures more quickly than diazepam . AAS will not eliminate the

  10. Cathepsin D inhibitors

    Directory of Open Access Journals (Sweden)

    M. Gacko

    2007-11-01

    Full Text Available Inhibitors of cathepsin D belong to chemical compounds that estrify carboxyl groups of the Asp33 and Asp231residues of its catalytic site, penta-peptides containing statin, i.e. the amino acid similar in structure to the tetraedric indirectproduct, and polypeptides found in the spare organs of many plants and forming permanent noncovalent complexes withcathepsin. Cathepsin D activity is also inhibited by alpha2-macroglobulin and antibodies directed against this enzyme.Methods used to determine the activity and concentration of these inhibitors and their analytical, preparative and therapeuticapplications are discussed.

  11. Annual Trapping Proposal 1985

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This Annual Trapping Plan for the 1984-1985 trapping season at Clarence Cannon NWR outlines rules and regulations for the trapping of beaver and muskrat on the...

  12. Annual Adjustment Factors

    Data.gov (United States)

    Department of Housing and Urban Development — The Department of Housing and Urban Development establishes the rent adjustment factors - called Annual Adjustment Factors (AAFs) - on the basis of Consumer Price...

  13. ASIST 2002 annual meeting

    CERN Multimedia

    Peek, R

    2003-01-01

    Review of discussions and presentations at the American Society for Information Science and Technology 2002 annual meeting. Topics covered included new models of scholarly publishing and the development of the semantic web (1 page).

  14. USRDS - Annual Data Report

    Data.gov (United States)

    U.S. Department of Health & Human Services — United States Renal Data System (USRDS) Annual Data Report Comprehensive statistics on chronic kidney disease and end-stage renal diseases in the United States...

  15. 2010 Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    None

    2010-01-01

    This annual report includes: an overview of Western; approaches for future hydropower and transmission service; major achievements in FY 2010; FY 2010 customer Integrated Resource Planning, or IRP, survey; and financial data.

  16. SIS - Annual Catch Limit

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Annual Catch Limit (ACL) dataset within the Species Information System (SIS) contains information and data related to management reference points and catch data.

  17. Annual General Canvass Statistics

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This data set contains annual quantities and value for all seafood products that are landed and sold by established seafood dealers and brokers in the Southeast...

  18. Natural gas annual 1994

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-11-17

    The Natural Gas Annual provides information on the supply and disposition of natural gas to a wide audience including industry, consumers, Federal and State agencies, and educational institutions. The 1994 data are presented in a sequence that follows natural gas (including supplemental supplies) from its production to its end use. This is followed by tables summarizing natural gas supply and disposition from 1990 to 1994 for each Census Division and each State. Annual historical data are shown at the national level.

  19. Emicizumab Prophylaxis in Hemophilia A with Inhibitors.

    Science.gov (United States)

    Oldenburg, Johannes; Mahlangu, Johnny N; Kim, Benjamin; Schmitt, Christophe; Callaghan, Michael U; Young, Guy; Santagostino, Elena; Kruse-Jarres, Rebecca; Negrier, Claude; Kessler, Craig; Valente, Nancy; Asikanius, Elina; Levy, Gallia G; Windyga, Jerzy; Shima, Midori

    2017-08-31

    Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (Phemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

  20. Inhibitors of histone demethylases

    DEFF Research Database (Denmark)

    Lohse, Brian; Kristensen, Jesper L; Kristensen, Line H

    2011-01-01

    Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the i...

  1. Protease inhibitors and beyond.

    Science.gov (United States)

    1997-03-01

    A new generation of protease inhibitors is entering studies. Abbott Lab's ABT-378 and Pharmacia/Upjohn's PNU-140690 are beginning clinical studies and both are designed to overcome resistance problems. Several companies are developing new compounds to inhibit reverse transcriptase, such as Bristol-Myers Squibb's lobucavir and Hoechst/Bayer's HBY097. Calanolide A, which will soon begin trials, has a different resistance pattern than other non-nucleoside reverse transcriptase inhibitors, which may be an important advantage. Several groups are developing compounds to inhibit the HIV zinc finger, such as Parke-Davis' compound, CI-1012; and a Dutch company who is developing Azodicarbonamide, a drug currently in phase I/II trials for people with advanced disease in Europe. HIV drugs to date have not been successful in blocking viral fusion. However, three new fusion inhibitors are showing promise within the laboratory: Pentafuside (currently in phase I trials), Fuji ImmunoPharmaceuticals' FP-21399 (currently in phase I trials), and ISIS Pharmaceuticals' ISIS 5320. A new class of drugs known as integrase inhibitors has been of interest to pharmaceutical companies for the past several years; only one drug, Aronex Pharmaceuticals' Zintevir, has reached phase I/II trials.

  2. Transglutaminase inhibitor from milk

    NARCIS (Netherlands)

    Jong, G.A.H. de; Wijngaards, G.; Koppelman, S.J.

    2003-01-01

    Cross-linking experiments of skimmed bovine milk with bacterial transglutaminase isolated from Streptoverticillium mobaraense showed only some degree of formation of high-molecular-weight casein polymers. Studies on the nature of this phenomenon revealed that bovine milk contains an inhibitor of

  3. HIV protease inhibitor resistance

    NARCIS (Netherlands)

    Wensing, Annemarie M.J.; Fun, Axel; Nijhuis, Monique

    2017-01-01

    HIV protease is pivotal in the viral replication cycle and directs the formation of mature infectious virus particles. The development of highly specific HIV protease inhibitors (PIs), based on thorough understanding of the structure of HIV protease and its substrate, serves as a prime example of

  4. Phosphodiesterase 4 inhibitors.

    Science.gov (United States)

    Zebda, Rema; Paller, Amy S

    2018-03-01

    Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration-approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety. Copyright © 2017. Published by Elsevier Inc.

  5. Proton-pump inhibitors

    African Journals Online (AJOL)

    Proton-pump inhibitors (PPIs) work by binding irreversibly to the. H+/K+-ATPase pump of the parietal cell, leading to inhibition of acid production in approximately 70% of active pumps.1The result is a dramatic increase in gastric pH mitigating the deleterious effects of acid in gastro-oesophageal reflux disease (GORD) and.

  6. Identification of Potential Herbal Inhibitor of Acetylcholinesterase Associated Alzheimer’s Disorders Using Molecular Docking and Molecular Dynamics Simulation

    Directory of Open Access Journals (Sweden)

    Chandrabhan Seniya

    2014-01-01

    Full Text Available Cholinesterase inhibitors (ChE-Is are the standard for the therapy of AD associated disorders and are the only class of approved drugs by the Food and Drug Administration (FDA. Additionally, acetylcholinesterase (AChE is the target for many Alzheimer’s dementia drugs which block the function of AChE but have some side effects. Therefore, in this paper, an attempt was made to elucidate cholinesterase inhibition potential of secondary metabolite from Cannabis plant which has negligible or no side effect. Molecular docking of 500 herbal compounds, against AChE, was performed using Autodock 4.2 as per the standard protocols. Molecular dynamics simulations have also been carried out to check stability of binding complex in water for 1000 ps. Our molecular docking and simulation have predicted high binding affinity of secondary metabolite (C28H34N2O6 to AChE. Further, molecular dynamics simulations for 1000 ps suggest that ligand interaction with the residues Asp72, Tyr70-121-334, and Phe288 of AChE, all of which fall under active site/subsite or binding pocket, might be critical for the inhibitory activity of AChE. This approach might be helpful to understand the selectivity of the given drug molecule in the treatment of Alzheimer's disease. The study provides evidence for consideration of C28H34N2O6 as a valuable small ligand molecule in treatment and prevention of AD associated disorders and further in vitro and in vivo investigations may prove its therapeutic potential.

  7. Natural gas annual 1997

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-10-01

    The Natural Gas Annual provides information on the supply and disposition of natural gas to a wide audience including industry, consumers, Federal and State agencies, and educational institutions. The 1997 data are presented in a sequence that follows natural gas (including supplemental supplies) from its production to its end use. This is followed by tables summarizing natural gas supply and disposition from 1993 to 1997 for each Census Division and each State. Annual historical data are shown at the national level. 27 figs., 109 tabs.

  8. International energy annual 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-02-01

    The International Energy Annual presents an overview of key international energy trends for production, consumption, imports, and exports of primary energy commodities in over 220 countries, dependencies, and areas of special sovereignty. Also included are population and gross domestic product data, as well as prices for crude oil and petroleum products in selected countries. Renewable energy reported in the International Energy Annual includes hydroelectric power, geothermal, solar, and wind electric power, biofuels energy for the US, and biofuels electric power for Brazil. New in the 1996 edition are estimates of carbon dioxide emissions from the consumption of petroleum and coal, and the consumption and flaring of natural gas. 72 tabs.

  9. NERSC Annual Report 2005

    Energy Technology Data Exchange (ETDEWEB)

    Hules (Ed.), John

    2006-07-31

    The National Energy Research Scientific Computing Center (NERSC) is the premier computational resource for scientific research funded by the DOE Office of Science. The Annual Report includes summaries of recent significant and representative computational science projects conducted on NERSC systems as well as information about NERSC's current and planned systems and services.

  10. Annual Report 2000

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2000-07-01

    The Institut Laue-Langevin (ILL) is an international research center using neutrons to probe the microscopic structure and dynamics of a broad range of materials. This annual report presents the ILL activities in 2000: the scientific highlights, the Millennium programme and the new developments, the workshops organized by the ILL, the experimental programme and the publications. (A.L.B.)

  11. FSAI Annual Report 2015

    OpenAIRE

    Food Safety Authority of Ireland

    2016-01-01

    THIS ANNUAL REPORT OUTLINES THE AUTHORITY’S EXTENSIVE WORK PROGRAMME IN 2015. IT DEMONSTRATES THE SIGNIFICANT ROLE THE AUTHORITY PLAYS IN ENCOURAGING THE HIGHEST STANDARDS IN FOOD PROVISION USING A COMBINATION OF SCIENCE BASED ACUMEN AND REGULATORY POWERS TO SAFEGUARD THE HEALTH AND INTERESTS OF CONSUMERS IN RELATION TO FOOD.

  12. Annual Integration Report 2013

    NARCIS (Netherlands)

    Jaco Dagevos; Willem Huijnk; Mérove Gijsberts

    2014-01-01

    Original title: Jaarrapport integratie 2013 The theme of the Annual Integration Report 2013 (Jaarrapport integratie 2013) is the participation of migrants on the labour market. The economic downturn is hitting the labour market hard. What does this mean for the labour market and income

  13. CSIR Annual report 1969

    CSIR Research Space (South Africa)

    CSIR

    1969-01-01

    Full Text Available This report presents the twenty fifth annual report of the Council for Scientific and Industrial Research. The report covers the period from the 1st January, 1969, to the 31st December 1969. Balance sheets and statements of income and expenditure...

  14. CSIR Annual report 1968

    CSIR Research Space (South Africa)

    CSIR

    1968-01-01

    Full Text Available This report presents the twenty fourth annual report of the Council for Scientific and Industrial Research. The report covers the period from the 1st January, 1968, to the 31st December 1968. Balance sheets and statements of income and expenditure...

  15. Annual report 1995

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-10-01

    The annual report from IKU (Continental Shelf Institute) in Norway deals with the market adjustment of research activities at the institute as a result of offshore cost-cutting policy in the petroleum industry. The market is about to shift focus from volume to competence. In practice, that means buying competence instead of project ideas or proposals

  16. NRCC annual report, 1979

    Energy Technology Data Exchange (ETDEWEB)

    1980-11-01

    This annual report of the National Research for Computation in Chemistry (NRCC) Division describes the program of research workshops, software development, and scientific research of the Division in 1979. This year marked the first full calendar year of activity of the Division. Initial staffing in the core scientific areas was completed by the addition of a crystallographer.

  17. CSIR Annual report 1967

    CSIR Research Space (South Africa)

    CSIR

    1967-01-01

    Full Text Available This report presents the twenty third annual report of the Council for Scientific and Industrial Research. The report covers the period from the 1st January, 1967, to the 31st December 1967. Balance sheets and statements of income and expenditure...

  18. CSIR Annual report 1980

    CSIR Research Space (South Africa)

    CSIR

    1980-01-01

    Full Text Available This report presents the thirty-sixth annual report of the CSIR. The report covers the period 1 January, 1980 to 31 December 1980. A balance sheet and statements of income and expenditure for the financial year ended 31st March 1980, certified...

  19. CSIR Annual report 1970

    CSIR Research Space (South Africa)

    CSIR

    1970-01-01

    Full Text Available This report presents the twenty sixth annual report of the Council for Scientific and Industrial Research. The report covers the period from the 1st January, 1970, to the 31st December 1970. Balance sheets and statements of income and expenditure...

  20. CSIR Annual report 1971

    CSIR Research Space (South Africa)

    CSIR

    1971-01-01

    Full Text Available This report presents the twenty seventh annual report of the Council for Scientific and Industrial Research. The report covers the period from the 1st January, 1971, to the 31st December 1971. Balance sheets and statements of income and expenditure...

  1. NERSC Annual Report 2002

    Energy Technology Data Exchange (ETDEWEB)

    Hules, John

    2003-01-31

    The National Energy Research Scientific Computing Center (NERSC) is the primary computational resource for scientific research funded by the DOE Office of Science. The Annual Report for FY2002 includes a summary of recent computational science conducted on NERSC systems (with abstracts of significant and representative projects), and information about NERSC's current and planned systems and service

  2. CSIR Annual report 1983

    CSIR Research Space (South Africa)

    CSIR

    1983-01-01

    Full Text Available This report presents the thirty ninth annual report of the CSIR. The report covers the period 1 January, 1983 to 31 December 1983. A balance sheet and statements of income and expenditure for the financial year ended 31st March 1983, certified...

  3. CSIR Annual report 1962

    CSIR Research Space (South Africa)

    CSIR

    1962-01-01

    Full Text Available This report presents the eighteenth annual report of the CSIR. The report covers the period 1 January, 1962 to 31 December 1962. A balance sheet and statements of income and expenditure for the financial year ended 31st March 1962, certified...

  4. Carolinas Communication Annual, 1998.

    Science.gov (United States)

    McLennan, David B.

    1998-01-01

    This 1998 issue of "Carolinas Communication Annual" contains the following articles: "Give Me That Old Time Religion?: A Study of Religious Themes in the Rhetoric of the Ku Klux Klan" (John S. Seiter); "The Three Stooges versus the Third Reich" (Roy Schwartzman); "Interdisciplinary Team Teaching: Implementing…

  5. CSIR Annual report 1966

    CSIR Research Space (South Africa)

    CSIR

    1966-01-01

    Full Text Available This report presents the twenty second annual report of the Council for Scientific and Industrial Research. The report covers the period from the 1st January, 1966, to the 31st December 1966. Balance sheets and statements of income and expenditure...

  6. Mail Office annual closure

    CERN Multimedia

    2013-01-01

    On the occasion of the annual closure of CERN, there will be no mail distributed on Friday 20 December 2013 but mail will be collected in the morning. Nevertheless, you will still be able to bring your outgoing mail to Building 555-R-002 until 12 noon.  

  7. CSIR Annual report 1963

    CSIR Research Space (South Africa)

    CSIR

    1963-01-01

    Full Text Available This report presents the nineteenth annual report of the Council for Scientific and Industrial Research. The report covers the period from the 1st January, 1963, to the 31st December 1963. Balance sheets and statements of income and expenditure...

  8. NERSC Annual Report 2004

    Energy Technology Data Exchange (ETDEWEB)

    Hules, John; Bashor, Jon; Yarris, Lynn; McCullough, Julie; Preuss, Paul; Bethel, Wes

    2005-04-15

    The National Energy Research Scientific Computing Center (NERSC) is the premier computational resource for scientific research funded by the DOE Office of Science. The Annual Report includes summaries of recent significant and representative computational science projects conducted on NERSC systems as well as information about NERSC's current and planned systems and services.

  9. International Energy Annual, 1992

    Energy Technology Data Exchange (ETDEWEB)

    1994-01-14

    This report is prepared annually and presents the latest information and trends on world energy production and consumption for petroleum, natural gas, coal, and electricity. Trade and reserves are shown for petroleum, natural gas, and coal. Prices are included for selected petroleum products. Production and consumption data are reported in standard units as well as British thermal units (Btu) and joules.

  10. CSIR Annual report 1981

    CSIR Research Space (South Africa)

    CSIR

    1981-01-01

    Full Text Available This report presents the thirty seventh annual report of the CSIR. The report covers the period 1 January, 1981 to 31 December 1981. A balance sheet and statements of income and expenditure for the financial year ended 31st March 1981, certified...

  11. CSIR Annual report 1982

    CSIR Research Space (South Africa)

    CSIR

    1982-01-01

    Full Text Available This report presents the thirty eighth annual report of the CSIR. The report covers the period 1 January, 1982 to 31 December 1982. A balance sheet and statements of income and expenditure for the financial year ended 31st March 1982, certified...

  12. Protective propensity of bacoside A and bromelain on renal cholinesterases, γ-Aminobutyric acid and serotonin level of Mus musculus intoxicated with dichlorvos.

    Science.gov (United States)

    Agarwal, Sonam; Chaudhary, Bharti; Bist, Renu

    2017-01-05

    Current study established a protective action of bacoside A and bromelain against the toxic effects of dichlorvos in kidneys of mice. Experimental design included five groups. The first group was control. Mice of groups II, III and IV were administered doses of dichlorvos, bromelain and bacoside A respectively. In group V, mice were treated with both the antioxidants (bacoside A and bromelain) and dichlorvos. After 21 days of exposure of different doses, levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), γ-aminobutyric acid (GABA) and serotonin were measured in renal tissues. Dichlorvos significantly reduced the kidney AChE (p bromelain followed by dichlorvos treatment in group V not only restored, but increased the renal cholinesterases and GABA level. Meanwhile, a significant decline in serotonin level (p bromelain occupy a tremendous antioxidant action in the mice kidneys and a combination of the same ameliorates the renal toxicity induced by dichlorvos. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Cholinesterase, tyrosinase inhibitory and antioxidant potential of randomly selected Umbelliferous plant species and chromatographic profile of Heracleum platytaenium Boiss. and Angelica sylvestris L. var. sylvestris

    Directory of Open Access Journals (Sweden)

    Orhan Ilkay Edrogan

    2016-01-01

    Full Text Available Neurobiological activity of the methanol extracts of thirteen Umbelliferae (Apiaceae plants was tested against acetylcholinesterase (AChE, butyrylcholinesterase (BChE, and tyrosinase (TYR using high-throughput screening technique. Although the extracts displayed none to low profile of inhibition against enzymes, the highest cholinesterase inhibition was observed with Heracleum platytaenium (32.52 ± 3.27 % for AChE and 46.16 ± 1.42 % for BChE at 100 μg mL-1. Since neurodegeneration is linked to oxidative damage, antioxidant potential of the extracts was searched through radical scavenging, metal-chelating capacity, and reducing power experiments and exerted modest levels of activity varying according to the method. The extracts had a better ability to scavenge nitric oxide radical (19.47 ± 2.09 % to 54.91 ± 1.98 %. Since these species are known to be rich in coumarins, our quantitative high-performance liquid chroatography (HPLC analysis indicated presence of xanthotoxin, angelicin, isopimpinellin, bergapten, and pimpinellin in Heracleum platytaenium and angelicin and imperatorin in Angelica sylvestris var. sylvestris.

  14. Increase of plasma insulin by racecadotril, an inhibitor of enkephalinase, in Wistar rats.

    Science.gov (United States)

    Wu, H T; Chang, C K; Cheng, K C; Chang, C H; Yeh, C H; Cheng, J T

    2010-04-01

    Racecadotril is known as an inhibitor of enkephalinase. Increase of plasma insulin by racecadotril has been observed in rats while the mechanism of the action remains obscure. In the present study, intravenous injection of male Wistar rats with racecadotril significantly decreased blood glucose levels. However, this effect of racecadotril was not modified by naloxone at the dose sufficient to block opioid receptors. Thus, the blood glucose-lowering action of racecadotril might be through an endogenous opioid independent mechanism. Otherwise, we found that C-peptide content was also raised by racecadotril in parallel with the increase of insulin in Wistar rats. Thus, the blood glucose-lowering action of racecadotril was related to insulin secretion, but not through the inhibition of plasma insulin degradation. In addition, racecadotril showed no direct effect on insulin secretion in isolated islets or cultured HIT-T15 beta cells. The increase of plasma insulin and blood glucose-lowering action induced by racecadotril were reduced by pretreatment with atropine and enhanced by physotigmine. Direct inhibition of cholinesterase was not observed in brain homogenates treated with racecadotril. Moreover, actions of racecadotril were significantly reduced in rats receiving hemicholinium-3 at a sufficient dose to decrease endogenous acetylcholine. Activation of cholinergic tone is possibly involved in the blood glucose-lowering effect of racecadotril. Our results suggested that racecadotril increased insulin secretion to lower blood glucose mainly via regulation of parasympathetic tone in Wistar rats. Georg Thieme Verlag KG Stuttgart New York.

  15. Treatment of Visual Hallucinations in Schizophrenia by Acetylcholinesterase Inhibitors: a case report

    Directory of Open Access Journals (Sweden)

    Ali Mohammadi

    2011-10-01

    Full Text Available "nSchizophrenia and various neurological disorders have some signs and symptoms. Visual hallucinations are one of such disorders. The related studies in some diseases for example Parkinson Disease and Lewy Body Dementia indicate that Acetylcholine (Ach plays a significant role in neuropsychiatric manifestation and its association with visual hallucination; therefore, visual hallucinations occur due to the depletion of Ach. Drug therapies such as Cholinesterase inhibitors (ChEIs for increasing Ach level may be beneficial in treating visual hallucination. AchEI's have been used in the treatment of visual hallucinations in Dementia and Parkinson's Disease. We thought that a similar Ach depletion may cause visual hallucinations in patients with schizophrenia and may provide a target for drug treatment. We had a patient with schizophrenia whose psychotic symptoms responded to the treatment plan, but her visual hallucination did not. However, the patient's visual hallucination successfully responded to Rivastigmine (AchEI. "nThis case illustrates the use of an AchEI in the treatment of refractory visual hallucinations in a patient with schizophrenia.

  16. [Cytoplasmic kinase inhibitors].

    Science.gov (United States)

    Mano, Hiroyuki

    2010-10-01

    Protein kinases play essential roles in the regulation of cell proliferation. Point mutations or/and fusions of protein kinases are frequently identified in human cancers, and targeting such activated kinases provides us with a chance to eradicate tumor cells. This was first proved by imatinib mesylate that inhibits ABL tyrosine kinase and, thereby, efficiently kills malignant cells in chronic myeloid leukemia. In addition, other clinical trials are ongoing for kinase inhibitors against EML4--ALK in lung cancer, JAK2 in myeloproliferative disorders and BRAF in malignant melanoma. Early reports indeed reveal that such targeting compounds are promising drugs for human cancers with activated kinases.

  17. 1988 Annual water management plan

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Ruby Lake NWR 1987 Annual Water Management Report 1988 Annual Water Management Plan. Includes 1987 weather summary, water availability forecast, summary of 1987...

  18. Annual Energy Review 2007

    Energy Technology Data Exchange (ETDEWEB)

    Seiferlein, Katherine E. [USDOE Energy Information Administration (EIA), Washington, DC (United States)

    2008-06-01

    The Annual Energy Review (AER) is the Energy Information Administration's (EIA) primary report of annual historical energy statistics. For many series, data begin with the year 1949. Included are data on total energy production, consumption, and trade; overviews of petroleum, natural gas, coal, electricity, nuclear energy, renewable energy, international energy, as well as financial and environment indicators; and data unit conversion tables. Publication of this report is required under Public Law 95–91 (Department of Energy Organization Act), Section 205(c), and is in keeping with responsibilities given to the EIA under Section 205(a)(2), which states: “The Administrator shall be responsible for carrying out a central, comprehensive, and unified energy data and information program which will collect, evaluate, assemble, analyze, and disseminate data and information....”

  19. Coal industry annual 1997

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-12-01

    Coal Industry Annual 1997 provides comprehensive information about US coal production, number of mines, prices, productivity, employment, productive capacity, and recoverable reserves. US Coal production for 1997 and previous years is based on the annual survey EIA-7A, Coal Production Report. This report presents data on coal consumption, coal distribution, coal stocks, coal prices, and coal quality for Congress, Federal and State agencies, the coal industry, and the general public. Appendix A contains a compilation of coal statistics for the major coal-producing States. This report includes a national total coal consumption for nonutility power producers that are not in the manufacturing, agriculture, mining, construction, or commercial sectors. 14 figs., 145 tabs.

  20. International energy annual 1997

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1999-04-01

    The International Energy Annual presents an overview of key international energy trends for production, consumption, imports, and exports of primary energy commodities in over 220 countries, dependencies, and areas of special sovereignty. Also included are population and gross domestic product data, as well as prices for crude oil and petroleum products in selected countries. Renewable energy reported in the International Energy Annual includes hydroelectric power and geothermal, solar, and wind electric power. Also included are biomass electric power for Brazil and the US, and biomass, geothermal, and solar energy produced in the US and not used for electricity generation. This report is published to keep the public and other interested parties fully informed of primary energy supplies on a global basis. The data presented have been largely derived from published sources. The data have been converted to units of measurement and thermal values (Appendices E and F) familiar to the American public. 93 tabs.

  1. NAGRA Annual report 2010

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2011-04-15

    This annual report presents the highlights of the activities carried out by the Swiss National Co-operative for the Disposal of Radioactive Wastes NAGRA during the year 2010. These include reviews by various commissions of the NAGRA co-operative's proposals for possible sites for nuclear waste repositories. Also, the enhancements made concerning information facilities for the general public at the co-operative's rock laboratories are mentioned. The operation of initial satellite-based precision measurement systems for movements in the earth's crust is noted. Organisational aspects and international co-operation are discussed. This annual report also looks at NAGRA's organisational structures and its commercial accounts. Appendices provide details on waste inventories and volumes and publications made in 2010. A selection of relevant internet addresses is also provided

  2. Renewable energy annual 1995

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-12-01

    The Renewable Energy Annual 1995 is the first in an expected series of annual reports the Energy Information Administration (EIA) intends to publish to provide a comprehensive assessment of renewable energy. This report presents the following information on the history, status, and prospects of renewable energy data: estimates of renewable resources; characterizations of renewable energy technologies; descriptions of industry infrastructures for individual technologies; evaluations of current market status; and assessments of near-term prospects for market growth. An international section is included, as well as two feature articles that discuss issues of importance for renewable energy as a whole. The report also contains a number of technical appendices and a glossary. The renewable energy sources included are biomass (wood), municipal solid waste, biomass-derived liquid fuels, geothermal, wind, and solar and photovoltaic.

  3. Annual General Asssembly

    CERN Multimedia

    2005-01-01

    All members and beneficiaries of the Pension Fund are invited to attend the Annual General Asssembly to be held in the CERN Council Chamber on Thursday 13 October 2005 at 14:30 The Agenda comprises: Opening Remarks (J. Bezemer) Results and presentation of the Annual Report 2004 - Role of asset classes in pension funds (C. Cuénoud) Copies of the 2004 Report are available from departmental secretariats. Package of measures aiming at equilibrating the Fund - Proposals by the Governing Board (J.-P. Matheys) Questions from members and beneficiaries Persons wishing to ask questions are encouraged to submit them, where possible, in writing in advance, addressed to Mr C. Cuénoud, Administrator of the Fund. Conclusions (J. Bezemer) As usual, participants are invited to drinks after the assembly. NB The minutes of the 2004 General Assembly are available from the Administration of the Fund (tel.(+4122)767 27 42; e-mail Sophia.Revol@cern.ch)

  4. Annual General Asssembly

    CERN Multimedia

    Pension Fund

    2005-01-01

    All members and beneficiaries of the Pension Fund are invited to attend the Annual General Asssembly to be held in the CERN Council Chamber on Thursday 13 October 2005 at 14:30 The Agenda comprises: Opening Remarks (J. Bezemer) Results and presentation of the Annual Report 2004 - Role of asset classes in pension funds (C. Cuénoud). Copies of the 2004 Report are available from departmental secretariats. Package of measures aiming at equilibrating the Fund - Proposals by the Governing Board (J.-P. Matheys). Questions from members and beneficiaries. Persons wishing to ask questions are encouraged to submit them, where possible, in writing in advance, addressed to Mr C. Cuénoud, Administrator of the Fund. Conclusions (J. Bezemer). As usual, participants are invited to drinks after the assembly. NB The minutes of the 2004 General Assembly are available from the Administration of the Fund (tel.(+4122)767 27 42; e-mail Sophia.Revol@cern.ch)

  5. Annual report 1991

    Energy Technology Data Exchange (ETDEWEB)

    Broda, R.; Lesniak, L.; Malecki, P.; Stachura, Z.; Wojciechowski, H. [eds.

    1992-12-31

    The material presented describing the scientific activities of the Henryk Niewodniczanski Institute of Nuclear Physics in 1991 is the first annual report in several years.The arrangement of the report from various departments reflect the present structure of the Institute and is meant to help in the future task of reconstructing the Institute. Few guidelines proposed by the editorial board gave the individual departments much freedom in selecting the material and choosing the volume and format of presentation. (author).

  6. 2008 annual merit review

    Energy Technology Data Exchange (ETDEWEB)

    None, None

    2009-01-18

    The 2008 DOE Vehicle Technologies Program Annual Merit Review was held February 25-28, 2008 in Bethesda, Maryland. The review encompassed all of the work done by the Vehicle Technologies Program: a total of 280 individual activities were reviewed, by a total of just over 100 reviewers. A total of 1,908 individual review responses were received for the technical reviews, and an additional 29 individual review responses were received for the plenary session review.

  7. TIARA annual report 1997

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Ryuichi; Saido, Masahiro; Nashiyama, Isamu [eds.] [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment] [and others

    1998-10-01

    This annual report describes research activities which have been performed with the JAERI TIARA (Takasaki Ion Accelerators for Advanced Radiation Application) facilities from April 1, 1997 to March 31, 1998. Summary reports of 90 papers and brief descriptions on the status of TIARA in the period are contained. A list of publications, the type of research collaborations and organization of TIARA are also given as appendices. (author)

  8. TIARA annual report 1998

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1999-10-01

    This annual report describes research and development activities which have been performed with the JAERI TIARA (Takasaki Ion Accelerators for Advanced Radiation Application) facilities from April 1, 1998 to March 31, 1999. Summary reports of 95 papers and brief descriptions on the status of TIARA in the period are contained. A list of publications, the type of research collaborations and organization of TIARA are also given as appendices. (author)

  9. NSLS annual report 1984

    Energy Technology Data Exchange (ETDEWEB)

    Klaffky, R.; Thomlinson, W. (eds.)

    1984-01-01

    The first comprehensive Annual Report of the National Synchrotron Light Source comes at a time of great activity and forward motion for the facility. In the following pages we outline the management changes that have taken place in the past year, the progress that has been made in the commissioning of the x-ray ring and in the enhanced utilization of the uv ring, together with an extensive discussion of the interesting scientific experiments that have been carried out.

  10. TIARA annual report 2000

    Energy Technology Data Exchange (ETDEWEB)

    Saidoh, Masahiro; Toraishi, Akio; Namba, Hideki (eds.) [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment] [and others

    2001-11-01

    This annual report describes research and development activities which have been performed with the JAERI TIARA (Takasaki Ion Accelerators for Advanced Radiation Application) facilities from April 1, 2000 to March 31, 2001. Summary reports of 103 papers and brief descriptions on the status of TIARA in the period are contained. A list of publications, the type of research collaborations and organization of TIARA are also given as appendices. (author)

  11. TIARA annual report 2001

    Energy Technology Data Exchange (ETDEWEB)

    Saidoh, Masahiro; Ohara, Yoshihiro; Namba, Hideki (eds.) [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment] [and others

    2002-11-01

    This annual report describes research and development activities which have been performed with the JAERI TIARA (Takasaki Ion Accelerators for Advanced Radiation Application) facilities from April 1, 2001 to March 31, 2002. Summary reports of 109 papers and brief descriptions on the status of TIARA in the period are contained. A list of publications, the type of research collaborations and organization of TIARA are also given as appendices. (author)

  12. TIARA annual report 1999

    Energy Technology Data Exchange (ETDEWEB)

    Saidoh, Masahiro; Toraishi, Akio; Itoh, Hisayoshi [eds.] [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment] [and others

    2000-10-01

    This annual report describes research and development activities which have been performed with the JAERI TIARA (Takasaki Ion Accelerators for Advanced Radiation Application) facilities from April 1, 1999 to March 31, 2000. Summary reports of 106 papers and brief descriptions on the status of TIARA in the period are contained. A list of publications, the type of research collaborations and organization of TIARA are also given as appendices. (author)

  13. NERSC 1998 annual report

    Energy Technology Data Exchange (ETDEWEB)

    Hules, John (ed.)

    1999-03-01

    This 1998 annual report from the National Scientific Energy Research Computing Center (NERSC) presents the year in review of the following categories: Computational Science; Computer Science and Applied Mathematics; and Systems and Services. Also presented are science highlights in the following categories: Basic Energy Sciences; Biological and Environmental Research; Fusion Energy Sciences; High Energy and Nuclear Physics; and Advanced Scientific Computing Research and Other Projects.

  14. TIARA annual report 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-11-01

    This annual report describes research activities which have been performed with the JAERI TIARA (Takasaki Ion Accelerators for Advanced Radiation Application) facilities from April 1, 1996 to March 31, 1997. Summary reports of 88 papers and 4 brief descriptions on the status of TIARA in the period are contained. A list of publications, the type of research collaborations and organization of TIARA are also given as appendices. (J.P.N.)

  15. 2012 CPES Annual Report

    OpenAIRE

    Virginia Tech. Center for Power Electronics Systems

    2012-01-01

    The Center for Power Electronics Systems at Virginia Tech is a research center dedicated to improving electrical power processing and distribution that impact systems of all sizes – from battery – operated electronics to vehicles to regional and national electrical distribution systems. Our mission is to provide leadership through global collaborative research and education for creating advanced electric power processing systems of the highest value to society. CPES, with annual research expe...

  16. De novo amplification within a silent human cholinesterase gene in a family subjected to prolonged exposure to organophosphorus insecticides

    Energy Technology Data Exchange (ETDEWEB)

    Prody, C.A.; Dreyfus, P.; Soreq, H. (Hebrew Univ., Jerusalem (Israel)); Zamir, R. (Hebrew Univ., Jerusalem (Israel) Tel-Aviv Univ. (Israel)); Zakut, H. (Tel-Aviv Univ. (Israel))

    1989-01-01

    A 100-fold DNA amplification in the CHE gene, coding for serum butyrylcholinesterase (BtChoEase), was found in a farmer expressing silent CHE phenotype. Individuals homozygous for this gene display a defective serum BtChoEase and are particularly vulnerable to poisoning by agricultural organophosphorus insecticides, to which all members of this family had long been exposed. DNA blot hybridization with regional BtChoEase cDNA probes suggested that the amplification was most intense in regions encoding central sequences within BtChoEase cDNA, whereas distal sequences were amplified to a much lower extent. This is in agreement with the onion skin model, based on amplification of genes in cultured cells and primary tumors. The amplification was absent in the grandparents but present at the same extent in one of their sons and in a grandson, with similar DNA blot hybridization patterns. In situ hybridization experiments localized the amplified sequences to the long arm of chromosome 3, close to the site where the authors previously mapped the CHE gene. Altogether, these observations suggest that the initial amplification event occurred early in embryogenesis, spermatogenesis, or oogenesis, where the CHE gene is intensely active and where cholinergic functioning was indicated to be physiologically necessary. These findings demonstrate a de novo amplification in apparently healthy individuals within an autosomal gene producing a target protein to an inhibitor.

  17. Uranium industry annual 1994

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-07-05

    The Uranium Industry Annual 1994 (UIA 1994) provides current statistical data on the US uranium industry`s activities relating to uranium raw materials and uranium marketing during that survey year. The UIA 1994 is prepared for use by the Congress, Federal and State agencies, the uranium and nuclear electric utility industries, and the public. It contains data for the 10-year period 1985 through 1994 as collected on the Form EIA-858, ``Uranium Industry Annual Survey.`` Data collected on the ``Uranium Industry Annual Survey`` (UIAS) provide a comprehensive statistical characterization of the industry`s activities for the survey year and also include some information about industry`s plans and commitments for the near-term future. Where aggregate data are presented in the UIA 1994, care has been taken to protect the confidentiality of company-specific information while still conveying accurate and complete statistical data. A feature article, ``Comparison of Uranium Mill Tailings Reclamation in the United States and Canada,`` is included in the UIA 1994. Data on uranium raw materials activities including exploration activities and expenditures, EIA-estimated resources and reserves, mine production of uranium, production of uranium concentrate, and industry employment are presented in Chapter 1. Data on uranium marketing activities, including purchases of uranium and enrichment services, and uranium inventories, enrichment feed deliveries (actual and projected), and unfilled market requirements are shown in Chapter 2.

  18. Methyl Jasmonate Induces Papain Inhibitor(s) in Tomato Leaves.

    Science.gov (United States)

    Bolter, C. J.

    1993-12-01

    Leaves of 18- to 24-d-old tomato (Lycopersicon esculentum) plants exposed to gaseous methyl jasmonate (MJ) for 24 h at 30[deg]C in continuous light contained high levels of soluble protein that inhibited papain. Chromatographic analysis demonstrated that the active protein had a molecular mass of 80 to 90 kD. Induction of papain inhibitor was directly related to the concentration of air-borne MJ up to a maximum of 0.1 [mu]L MJ per treatment and depended on the duration of exposure up to 18 h. Inhibitor activity in plants treated for less than 18 h increased with time after treatment. Levels remained constant for up to 4 d after treatment, after which time activity decreased. The youngest leaf, leaf 5, consistently lost activity at a faster rate than older, lower leaves. Inhibitor concentration in all leaves was reduced to minimum levels by 11 d after MJ treatment, but did not return to control levels. Treatment with MJ in the dark did induce inhibitor activity, but at a significantly lower rate. Polyclonal antibodies raised to purified potato tuber skin cysteine proteinase inhibitors (CPI) cross-reacted with the tomato inhibitor, suggesting that the tomato papain inhibitor and the potato CPI are closely related. No papain inhibitor activity was observed in extracts from wounded tomato leaves, nor was there any immunoreactivity with antibodies raised to potato tuber skin CPI.

  19. The SRTR/OPTN Annual Data Report

    Science.gov (United States)

    ... Annual Data Report The SRTR/OPTN Annual Data Report Statistics on donation and transplantation in the United ... US in 2015. The SRTR/OPTN Annual Data Report SRTR/OPTN Annual Data Report Learn more from ...

  20. Association of Proton Pump Inhibitors Usage with Risk of Pneumonia in Dementia Patients.

    Science.gov (United States)

    Ho, Sai-Wai; Teng, Ying-Hock; Yang, Shun-Fa; Yeh, Han-Wei; Wang, Yu-Hsun; Chou, Ming-Chih; Yeh, Chao-Bin

    2017-07-01

    To determine the association between usages of proton pump inhibitors (PPIs) and subsequent risk of pneumonia in dementia patients. Retrospective cohort study. Taiwanese National Health Insurance Research Database. The study cohort consisted of 786 dementia patients with new PPI usage and 786 matched dementia patients without PPI usage. The study endpoint was defined as the occurrence of pneumonia. The Cox proportional hazard model was used to estimate the pneumonia risk. Defined daily dose methodology was applied to evaluate the cumulative and dose-response relationships of PPI. Incidence of pneumonia was higher among patients with PPI usage (adjusted hazard ratio (HR) = 1.89; 95% CI = 1.51-2.37). Cox model analysis also demonstrated that age (adjusted HR = 1.05; 95% CI = 1.03-1.06), male gender (adjusted HR = 1.57; 95% CI = 1.25-1.98), underlying cerebrovascular disease (adjusted HR = 1.30; 95% CI = 1.04-1.62), chronic pulmonary disease (adjusted HR = 1.39; 95% CI = 1.09-1.76), congestive heart failure (adjusted HR = 1.54; 95% CI = 1.11-2.13), diabetes mellitus (adjusted HR = 1.54; 95% CI = 1.22-1.95), and usage of antipsychotics (adjusted HR = 1.29; 95% CI = 1.03-1.61) were independent risk factors for pneumonia. However, usage of cholinesterase inhibitors and histamine receptor-2 antagonists were shown to decrease pneumonia risk. PPI usage in dementia patients is associated with an 89% increased risk of pneumonia. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

  1. NERSC 2001 Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    Hules, John (editor)

    2001-12-12

    The National Energy Research Scientific Computing Center (NERSC) is the primary computational resource for scientific research funded by the DOE Office of Science. The Annual Report for FY2001 includes a summary of recent computational science conducted on NERSC systems (with abstracts of significant and representative projects); information about NERSC's current systems and services; descriptions of Berkeley Lab's current research and development projects in applied mathematics, computer science, and computational science; and a brief summary of NERSC's Strategic Plan for 2002-2005.

  2. Nordel annual report 2003

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2004-06-01

    Nordel is a body for co-operation between the transmission system operators (TSO's) in Denmark, Finland, Iceland, Norway and Sweden with the primary objective to create conditions for and develop an efficient and harmonised Nordic electricity market, regardless of national borders. Furthermore, Nordel serves as forum for contact between the TSOs and representatives of the market players in the Nordic countries. The statistical part of Nordel's annual report includes data about: Exchange of electricity; Gross consumption; Electricity generation; Installed capacity; Generation of condensing power; Net consumption; Transmission capacity; Pumped storage power; Losses; Occasional power to electric boilers; Total consumption; CHP generation. (BA)

  3. Annual Energy Review 2001

    Energy Technology Data Exchange (ETDEWEB)

    Seiferlein, Katherine E. [USDOE Energy Information Administration (EIA), Washington, DC (United States)

    2002-11-01

    The Annual Energy Review (AER) is a statistical history of energy activities in the United States. It documents trends and milestones in U.S. energy production, trade, storage, pricing, and consumption. Each new year of data that is added to the time series—which now reach into 7 decades—extends the story of how Americans have acquired and used energy. It is a story of continual change as the Nation's economy grew, energy requirements expanded, resource availability shifted, and interdependencies developed among nations.

  4. Institute annual report 2004

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2005-07-01

    The mission of the ITU (Institute for Transuranium Elements) is to protect the European citizen against risk associated with the handling and storage of highly radioactive elements. The JRC (Joint Research Center) provide customer-driven scientific and technical support for the conception, development, implementation and monitoring of EU policies. In this framework this annual report presents the TU actions in: basic actinide research, spent fuel characterization, safety of nuclear fuels, partitioning and transmutation, alpha-immunotherapy/radiobiology, measurement of radioactivity in the environment, safeguards research and development. (A.L.B.)

  5. Annual Energy Review 2010

    Energy Technology Data Exchange (ETDEWEB)

    None

    2011-10-01

    This twenty-ninth edition of the Annual Energy Review (AER) presents the U.S. Energy Information Administration’s (EIA) most comprehensive look at integrated energy statistics. The summary statistics on the Nation’s energy production, consumption, trade, stocks, and prices cover all major energy commodities and all energy-consuming sectors of the U.S. economy from 1949 through 2010. The AER is EIA’s historical record of energy statistics and, because the coverage spans six decades, the statistics in this report are well-suited to long-term trend analysis.

  6. International energy annual 1995

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-12-01

    The International Energy Annual presents information and trends on world energy production and consumption for petroleum, natural gas, coal, and electricity. Production and consumption data are reported in standard units as well as British thermal units (Btu). Trade and reserves are shown for petroleum, natural gas, and coal. Data are provided on crude oil refining capacity and electricity installed capacity by type. Prices are included for selected crude oils and for refined petroleum products in selected countries. Population and Gross Domestic Product data are also provided.

  7. Renewable energy annual 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-03-01

    This report presents summary data on renewable energy consumption, the status of each of the primary renewable technologies, a profile of each of the associated industries, an analysis of topical issues related to renewable energy, and information on renewable energy projects worldwide. It is the second in a series of annual reports on renewable energy. The renewable energy resources included in the report are biomass (wood and ethanol); municipal solid waste, including waste-to-energy and landfill gas; geothermal; wind; and solar energy, including solar thermal and photovoltaic. The report also includes various appendices and a glossary.

  8. NPL 1999 Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    None

    2000-01-01

    OAK-B135 NPL 1999 Annual Report. The Nuclear Physics Laboratory at the University of Washington in Seattle pursues a broad program of nuclear physics research. Research activities are conducted locally and at remote sites. The current program includes ''in-house'' research on nuclear collisions using the local tandem Van de Graaff and superconducting linac accelerators as well as local and remote non-accelerator research on fundamental symmetries and weak interactions and user-mode research on relativistic heavy ions at large accelerator facilities around the world.

  9. Annual report to Congress

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1992-03-01

    This is the eighth annual report submitted by the Office of Civilian Radioactive Waste Management (OCRWM) to Congress. It covers activities and expenditures during Fiscal Year 1991, which ended September 30, 1991. Chapter 1 of this report describes OCRWM`s mission and objectives. Chapters 2 through 8 cover the following topics: earning public trust and confidence; geological disposal; monitored retrieval storage; transportation; systems integration and regulatory compliance; international programs; and program management. Financial statements for the Nuclear Waste Fund are presented in Chapter 9.

  10. Proteinase inhibitors in Brazilian leguminosae

    Directory of Open Access Journals (Sweden)

    C. A. M. Sampaio

    1991-01-01

    Full Text Available Serine proteinase inhitors, in the seeds of several Leguminosae from the Pantanal region (West Brazil, were studied using bovine trypsin, a digestive enzyme, Factor XIIa and human plasma Kallikrein, two blood clotting factors. The inhibitors were purified from Enterolobium contortisiliquum (Mr=23,000, Torresea cearensis (Mr = 13,000, Bauhinia pentandra (Mr = 20,000 and Bauhinia bauhinioides (Mr = 20,000. E. contortisiliquum inhibitor inactivates all three enzymes, whereas the T. cearensis inhibitor inactivates trypsin and Factor XSSa, but does nor affect plasma kallikrein; both Bauhinia inhibitors, on the other hand, inactivate trypsin and plasma kallikrein but only the Bpentandra inhibitor affects Factor XIIa. Ki values were calculated between 10 [raised to the power of] -7 and 10 [raised to the power of] -8 M.

  11. Accumulation of current-use pesticides, cholinesterase inhibition and reduced body condition in juvenile one-sided livebearer fish (Jenynsia multidentata) from the agricultural Pampa region of Argentina.

    Science.gov (United States)

    Brodeur, Julie Céline; Sanchez, Marisol; Castro, Luciana; Rojas, Dante Emanuel; Cristos, Diego; Damonte, María Jimena; Poliserpi, María Belén; D'Andrea, María Florencia; Andriulo, Adrián Enrique

    2017-10-01

    The aim of this study was to characterize the level and nature of the pesticide contamination received by one-sided livebearer fish (Jenynsia multidentata) from a watercourse situated within the main agricultural region of Argentina, and to assess the effects of this contamination on fish health. Juvenile one-sided livebearer fish (Jenynsia multidentata) were collected in December 2011 and March 2012 from three sites along the Pergamino River. Pesticide contamination was characterized by extracting whole fish and analytically determining thirty different pesticide molecules. The biomarkers catalase, glutathione-S-transferase, and cholinesterases were assessed. Body condition was calculated as an estimate of the amount of energy reserves possessed by the fish. Seventeen different pesticides were detected in fish tissues with 81% of captured animals containing at least one pesticide molecule. The pyrethroid insecticides fenvalerate and bifenthrin were most frequently detected, being respectively found in 41.8 and 36.4% of samples tested. Highly toxic dichlorvos and pirimiphos-methyl were detected. Differential levels of contamination could not be established amongst sites but were observed within sites amongst the two sampling dates. The months when pesticide residues were most abundant from in Site A and B corresponded to the months when body condition was at its lowest in the two sites. The inhibition of Che activity in March when body condition was reduced also points to a role of insecticide contamination in the reduction of body condition. These findings provide strong new evidence that current-used agricultural pesticides can accumulate in wild fish and impact their health and energetics. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Development of a Physiologically Based Pharmacokinetic and Pharmacodynamic Model to Determine Dosimetry and Cholinesterase Inhibition for a Binary Mixture of Chlorpyrifos and Diazinon in the Rat

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck; Poet, Torka S.

    2008-05-01

    Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models have been developed and validated for the organophosphorus (OP) insecticides chlorpyrifos (CPF) and diazinon (DZN). Based on similar pharmacokinetic and mode of action properties it is anticipated that these OPs could interact at a number of important metabolic steps including: CYP450 mediated activation/detoxification, and blood/tissue cholinesterase (ChE) binding/inhibition. We developed a binary PBPK/PD model for CPF, DZN and their metabolites based on previously published models for the individual insecticides. The metabolic interactions (CYP450) between CPF and DZN were evaluated in vitro and suggests that CPF is more substantially metabolized to its oxon metabolite than is DZN. These data are consistent with their observed in vivo relative potency (CPF>DZN). Each insecticide inhibited the other’s in vitro metabolism in a concentration-dependent manner. The PBPK model code used to described the metabolism of CPF and DZN was modified to reflect the type of inhibition kinetics (i.e. competitive vs. non-competitive). The binary model was then evaluated against previously published rodent dosimetry and ChE inhibition data for the mixture. The PBPK/PD model simulations of the acute oral exposure to single- (15 mg/kg) vs. binary-mixtures (15+15 mg/kg) of CFP and DZN at this lower dose resulted in no differences in the predicted pharmacokinetics of either the parent OPs or their respective metabolites; whereas, a binary oral dose of CPF+DZN at 60+60 mg/kg did result in observable changes in the DZN pharmacokinetics. Cmax was more reasonably fit by modifying the absorption parameters. It is anticipated that at low environmentally relevant binary doses, most likely to be encountered in occupational or environmental related exposures, that the pharmacokinetics are expected to be linear, and ChE inhibition dose-additive.

  13. Changes of serum pancreatic stone protein and cholinesterase contents in children with sepsis and their correlation with systemic inflammatory response and target organ damage

    Directory of Open Access Journals (Sweden)

    Zhi-Hong Ren

    2017-10-01

    Full Text Available Objective: To study the changes of serum pancreatic stone protein (PSP and cholinesterase (ChE contents in children with sepsis and their correlation with systemic inflammatory response and target organ damage. Methods: A total of 64 children with sepsis who were treated in the hospital between January 2015 and January 2017 were selected as observation group, and 50 healthy children who received vaccination in the hospital during the same period were selected as normal control group. The contents of PSP, ChE, inflammatory factors as well as liver and kidney function indexes in the two groups were detected. Pearson test was used to assess the correlation of serum PSP and ChE contents with systemic inflammatory response and target organ damage in children with sepsis. Results: Serum PSP content of observation group was higher than that of control group while ChE content was lower than that of control group; serum inflammatory factors PCT, CRP, IL-1, IL-6 and IL-10 contents of observation group were higher than those of normal control group; liver function indexes TBIL, ALT and AST contents were higher than those of normal control group; kidney function indexes Scr and BUN contents were higher than those of normal control group. Pearson test showed that the serum PSP and ChE contents in children with sepsis were directly correlated with the systemic inflammatory response as well as liver and renal function injury. Conclusion: Serum PSP content significantly increases while ChE content significantly decreases in children with sepsis and the specific change is directly correlated with the overall disease severity.

  14. Studies on the molecular dissection of human cholinesterase variants and their genomic origins. Midterm report, 1 June 1994-31 May 1995

    Energy Technology Data Exchange (ETDEWEB)

    Soreq, H.

    1995-06-01

    Research has been focused on the human cholinesterase genes, their variant protein products and the biological roles of these proteins in different tissue - and cell types. To elucidate the biochemical properties and biological functions of this large array of ChE variants, we employed microinjected oocytes and transiently transgenic embryos of Xenopus laevis. This has led to the demonstration that the C-terminal peptide characteristic of the brain and muscle form of acetyicholinesterase (AChE) and butyrylcholinesterase (BuChE) leads to synaptic targeting of these enzymes. Moreover, we were able to show that AChE exerts a morphogenic action on synapse development. The biochemical and biological functions of the BCHE gene and its BuChE protein product were approached by a combination of Xenopus oocyte expression and molecular genetics. Substitution of Asp at position 70 in BuChE by Gly creates an enzyme incapable of hydrolyzing succinylcholine, unlike the native enzyme. This structure-function relationship explained the known clinical syndrome of succinylcholine apnea. The next step was to replace the BuChE peptide harboring Asp70 with that of AChE. This introduced charge modification in the resultant active chimera and explained many of the differences between AChE and BuChE with respect to drug and poison sensitivities. A population diversity study revealed 11% heterozygotes for Asp/Gly70 among Israelis and shed new light on individual variabilities noted for the newly tested anti-AChE drugs, examined for their potential in Alzheimer`s therapy. Our current efforts are to extend these studies to elucidate the protective roles of these proteins.

  15. It All Starts at the Ends: Multifaceted Involvement of C- and N-Terminally Modified Cholinesterases in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Amit Berson

    2010-10-01

    Full Text Available In Alzheimer’s disease (AD, premature demise of acetylcholine-producing neurons and the consequent decline of cholinergic transmission associate with the prominent cognitive impairments of affected individuals. However, the enzymatic activities of acetylcholinesterase (AChE and butyrylcholinesterase (BChE are altered rather late in the disease progress. This raised questions regarding the causal involvement of AChE and BChE in AD. Importantly, single nucleotide polymorphisms (SNPs, alternative splicing, and alternate promoter usage generate complex expression of combinatorial cholinesterase (ChE variants, which called for testing the roles of specific variants in AD pathogenesis. We found accelerated amyloid fibril formation in engineered mice with enforced over-expression of the AChE-S splice variant which includes a helical C-terminus. In contrast, the AChE-R variant, which includes a naturally unfolded C-terminus, attenuated the oligomerization of amyloid fibrils and reduced amyloid plaque formation and toxicity. An extended N-terminus generated by an upstream promoter enhanced the damage caused by N-AChE-S, which in cell cultures induced caspases and GSK3 activation, tau hyperphosphorylation, and apoptosis. In the post-mortem AD brain, we found reduced levels of the neuroprotective AChE-R and increased levels of the neurotoxic N-AChE-S, suggesting bimodal contribution to AD progress. Finally, local unwinding of the α-helical C-terminal BChE peptide and loss of function of the pivotal tryptophan at its position 541 impair amyloid fibril attenuation by the common BChE-K variant carrying the A539T substitution, in vitro. Together, our results point to causal yet diverse involvement of the different ChEs in the early stages of AD pathogenesis. Harnessing the neuroprotective variants while reducing the levels of damaging ones may hence underlie the development of novel therapeutics.

  16. CMS Annual Report 2004

    Energy Technology Data Exchange (ETDEWEB)

    de la Rubia, T D; Shang, S P; Rennie, G; Fluss, M; Westbrook, C

    2005-07-29

    Glance at the articles in this report, and you will sense the transformation that is reshaping the landscape of materials science and chemistry. This transformation is bridging the gaps among chemistry, materials science, and biology--ushering in a wealth of innovative technologies with broad scientific impact. The emergence of this intersection is reinvigorating our strategic investment into areas that build on our strength of interdisciplinary science. It is at the intersection that we position our strategic vision into a future where we will provide radical materials innovations and solutions to our national-security programs and other sponsors. Our 2004 Annual Report describes how our successes and breakthroughs follow a path set forward by our strategic plan and four organizing research themes, each with key scientific accomplishments by our staff and collaborators. We have organized this report into two major sections: research themes and our dynamic teams. The research-theme sections focus on achievements arising from earlier investments while addressing future challenges. The dynamic teams section illustrates the directorate's organizational structure of divisions, centers, and institutes that support a team environment across disciplinary and institutional boundaries. The research presented in this annual report gives substantive examples of how we are proceeding in each of these four theme areas and how they are aligned with our national-security mission. By maintaining an organizational structure that offers an environment of collaborative problem-solving opportunities, we are able to nurture the discoveries and breakthroughs required for future successes.

  17. Annual Energy Review 2005

    Energy Technology Data Exchange (ETDEWEB)

    Seiferlein, Katherine E. [USDOE Energy Information Administration (EIA), Washington, DC (United States)

    2006-07-01

    The Annual Energy Review (AER) is the Energy Information Administration's (EIA) primary report of annual historical energy statistics. For many series, data begin with the year 1949. Included are data on total energy production, consumption, and trade; overviews of petroleum, natural gas, coal, electricity, nuclear energy, renewable energy, international energy, as well as financial and environment indicators; and data unit conversion tables. Publication of this report is required under Public Law 95–91 (Department of Energy Organization Act), Section 205(c), and is in keeping with responsibilities given to the EIA under Section 205(a)(2), which states: “The Administrator shall be responsible for carrying out a central, comprehensive, and unified energy data and information program which will collect, evaluate, assemble, analyze, and disseminate data and information....” The AER is intended for use by Members of Congress, Federal and State agencies, energy analysts, and the general public. EIA welcomes suggestions from readers regarding data series in the AER and in other EIA publications.

  18. Annual Energy Review 2004

    Energy Technology Data Exchange (ETDEWEB)

    Seiferlein, Katherine E. [USDOE Energy Information Administration (EIA), Washington, DC (United States)

    2005-08-01

    The Annual Energy Review (AER) is the Energy Information Administration's (EIA) primary report of annual historical energy statistics. For many series, data begin with the year 1949. Included are data on total energy production, consumption, and trade; overviews of petroleum, natural gas, coal, electricity, nuclear energy, renewable energy, international energy, as well as financial and environment indicators; and data unit conversion tables. Publication of this report is required under Public Law 95–91 (Department of Energy Organization Act), Section 205(c), and is in keeping with responsibilities given to the EIA under Section 205(a)(2), which states: “The Administrator shall be responsible for carrying out a central, comprehensive, and unified energy data and information program which will collect, evaluate, assemble, analyze, and disseminate data and information....” The AER is intended for use by Members of Congress, Federal and State agencies energy analysts, and the general public. EIA welcomes suggestions from readers regarding data series in the AER and in other EIA publications.

  19. Annual Energy Review 2006

    Energy Technology Data Exchange (ETDEWEB)

    Seiferlein, Katherine E. [USDOE Energy Information Administration (EIA), Washington, DC (United States)

    2007-06-01

    The Annual Energy Review (AER) is the Energy Information Administration's (EIA) primary report of annual historical energy statistics. For many series, data begin with the year 1949. Included are data on total energy production, consumption, and trade; overviews of petroleum, natural gas, coal, electricity, nuclear energy, renewable energy, international energy, as well as financial and environment indicators; and data unit conversion tables. Publication of this report is required under Public Law 95–91 (Department of Energy Organization Act), Section 205(c), and is in keeping with responsibilities given to the EIA under Section 205(a)(2), which states: “The Administrator shall be responsible for carrying out a central, comprehensive, and unified energy data and information program which will collect, evaluate, assemble, analyze, and disseminate data and information....” The AER is intended for use by Members of Congress, Federal and State agencies, energy analysts, and the general public. EIA welcomes suggestions from readers regarding data series in the AER and in other EIA publications.

  20. Annual Energy Review 2009

    Energy Technology Data Exchange (ETDEWEB)

    Fichman, Barbara T. [USDOE Energy Information Administration (EIA), Washington, DC (United States)

    2010-08-01

    The Annual Energy Review (AER) is the U.S. Energy Information Administration's (EIA) primary report of annual historical energy statistics. For many series, data begin with the year 1949. Included are statistics on total energy production, consumption, trade, and energy prices; overviews of petroleum, natural gas, coal, electricity, nuclear energy, renewable energy, and international energy; financial and environment indicators; and data unit conversions. Publication of this report is required under Public Law 95–91 (Department of Energy Organization Act), Section 205(c), and is in keeping with responsibilities given to the EIA under Section 205(a)(2), which states: “The Administrator shall be responsible for carrying out a central, comprehensive, and unified energy data and information program which will collect, evaluate, assemble, analyze, and disseminate data and information....” The AER is intended for use by Members of Congress, Federal and State agencies, energy analysts, and the general public. EIA welcomes suggestions from readers regarding the content of the AER and other EIA publications.

  1. Annual Energy Review 2011

    Energy Technology Data Exchange (ETDEWEB)

    Fichman, Barbara T. [USDOE Energy Information Administration (EIA), Washington, DC (United States)

    2012-09-01

    The Annual Energy Review (AER) is the U.S. Energy Information Administration's (EIA) primary report of annual historical energy statistics. For many series, data begin with the year 1949. Included are statistics on total energy production, consumption, trade, and energy prices; overviews of petroleum, natural gas, coal, electricity, nuclear energy, and renewable energy; financial and environment indicators; and data unit conversions. Publication of this report is required under Public Law 95–91 (Department of Energy Organization Act), Section 205(c), and is in keeping with responsibilities given to the EIA under Section 205(a)(2), which states: “The Administrator shall be responsible for carrying out a central, comprehensive, and unified energy data and information program which will collect, evaluate, assemble, analyze, and disseminate data and information....” The AER is intended for use by Members of Congress, Federal and State agencies, energy analysts, and the general public. EIA welcomes suggestions from readers regarding the content of the AER and other EIA publications.

  2. ANNUAL GENERAL ASSEMBLY

    CERN Multimedia

    2001-01-01

    All members and beneficiaries of the Pension Fund are invited to attend the Annual General Asssembly to be held in the CERN Auditorium on Wednesday 3 October 2001 at 14.30 hrs The Agenda comprises:   Opening Remarks (P. Levaux) Some aspects of risk in a pension fund (C. Cuénoud) Annual Report 2000: Presentation and results (C. Cuénoud) Copies of the Report are available from divisional secretariats. Results of the actuarial reviews (G. Maurin) Questions from members and beneficiaries Persons wishing to ask questions are encouraged to submit them, where possible, in writing in advance, addressed to Mr C. Cuénoud, Administrator of the Fund. Conclusions (P. Levaux) As usual, participants are invited to drinks after the assembly. NB The minutes of the 2000 General Assembly are available from the Administration of the Fund (tel. + 41 22 767 91 94; e-mail Graziella.Praire@cern.ch) The English version will be published next week.

  3. Annual Energy Review 1993

    Energy Technology Data Exchange (ETDEWEB)

    1994-07-14

    This twelfth edition of the Annual Energy Review (AER) presents the Energy Information Administration`s historical energy statistics. For most series, statistics are given for every year from 1949 through 1993. Because coverage spans four and a half decades, the statistics in this report are well-suited to long-term trend analyses. The AER is comprehensive. It covers all major energy activities, including consumption, production, trade, stocks, and prices, for all major energy commodities, including fossil fuels and electricity. The AER also presents Energy Information Administration (EIA) statistics on some renewable energy sources. EIA estimates that its consumption series include about half of the renewable energy used in the United States. For a more complete discussion of EIA`s renewables data, see p. xix, ``Introducing Expanded Coverage of Renewable Energy Data Into the Historical Consumption Series.`` Copies of the 1993 edition of the Annual Energy Review may be obtained by using the order form in the back of this publication. Most of the data in the 1993 edition also are available on personal computer diskette. For more information about the diskettes, see the back of this publication. In addition, the data are available as part of the National Economic, Social, and Environmental Data Bank on a CD-ROM. For more information about the data bank, contact the US Department of Commerce Economics and Statistics Administration, on 202-482-1986.

  4. Electric power annual 1992

    Energy Technology Data Exchange (ETDEWEB)

    1994-01-06

    The Electric Power Annual presents a summary of electric utility statistics at national, regional and State levels. The objective of the publication is to provide industry decisionmakers, government policymakers, analysts and the general public with historical data that may be used in understanding US electricity markets. The Electric Power Annual is prepared by the Survey Management Division; Office of Coal, Nuclear, Electric and Alternate Fuels; Energy Information Administration (EIA); US Department of Energy. ``The US Electric Power Industry at a Glance`` section presents a profile of the electric power industry ownership and performance, and a review of key statistics for the year. Subsequent sections present data on generating capability, including proposed capability additions; net generation; fossil-fuel statistics; retail sales; revenue; financial statistics; environmental statistics; electric power transactions; demand-side management; and nonutility power producers. In addition, the appendices provide supplemental data on major disturbances and unusual occurrences in US electricity power systems. Each section contains related text and tables and refers the reader to the appropriate publication that contains more detailed data on the subject matter. Monetary values in this publication are expressed in nominal terms.

  5. Areva, annual report 2004

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2004-07-01

    This annual report contains information on AREVA objectives, prospects and strategies, particularly in chapters 4 and 7. This information is a not meant as a presentation of past performance data and should not be interpreted as a guarantee that events or data set forth herein are assured or that objectives will be met. Forward looking statements made in this document also address known and unknown risks, uncertainties and other factors that could, were they to translate into fact, cause AREVA future financial performance, operating performance and production to differ significantly from the objectives presented or suggested herein. Those factors include, in particular, changes in international, economic or market conditions, as well as risk factors presented in Section 4.14.3. Neither AREVA nor the AREVA group is committing to updating forward looking statements or information contained in the annual report. This annual report contains information on the markets, market shares and competitive position of the AREVA group. Unless otherwise indicated, all historical data and forward looking information are based on Group estimates (source: AREVA) and are provided as examples only. To AREVA knowledge, no report is available on the AREVA group markets that is sufficiently complete or objective to serve as a sole reference source. The AREVA group developed estimates based on several sources, including in-house studies and reports, statistics provided by international organizations and professional associations, data published by competitors and information collected by AREVA subsidiaries. The main sources, studies and reports used include (i) the International Atomic Energy Agency (IAEA), the International Energy Agency (IEA), the World Nuclear Association (WNA), the Nuclear Energy Institute (NEA), Nuclear Assurance Corporation (NAC), the European Atomic Energy Community (Euratom) and the Commissariat a l'Energie Atomique (CEA) for the nuclear business; and (ii

  6. Annual Energy Review 1999

    Energy Technology Data Exchange (ETDEWEB)

    Seiferlein, Katherine E. [USDOE Energy Information Administration (EIA), Washington, DC (United States)

    2000-07-01

    A generation ago the Ford Foundation convened a group of experts to explore and assess the Nation’s energy future, and published their conclusions in A Time To Choose: America’s Energy Future (Cambridge, MA: Ballinger, 1974). The Energy Policy Project developed scenarios of U.S. potential energy use in 1985 and 2000. Now, with 1985 well behind us and 2000 nearly on the record books, it may be of interest to take a look back to see what actually happened and consider what it means for our future. The study group sketched three primary scenarios with differing assumptions about the growth of energy use. The Historical Growth scenario assumed that U.S. energy consumption would continue to expand by 3.4 percent per year, the average rate from 1950 to 1970. This scenario assumed no intentional efforts to change the pattern of consumption, only efforts to encourage development of our energy supply. The Technical Fix scenario anticipated a “conscious national effort to use energy more efficiently through engineering know-how." The Zero Energy Growth scenario, while not clamping down on the economy or calling for austerity, incorporated the Technical Fix efficiencies plus additional efficiencies. This third path anticipated that economic growth would depend less on energy-intensive industries and more on those that require less energy, i.e., the service sector. In 2000, total energy consumption was projected to be 187 quadrillion British thermal units (Btu) in the Historical Growth case, 124 quadrillion Btu in the Technical Fix case, and 100 quadrillion Btu in the Zero Energy Growth case. The Annual Energy Review 1999 reports a preliminary total consumption for 1999 of 97 quadrillion Btu (see Table 1.1), and the Energy Information Administration’s Short-Term Energy Outlook (April 2000) forecasts total energy consumption of 98 quadrillion Btu in 2000. What energy consumption path did the United States actually travel to get from 1974, when the scenarios were drawn

  7. Nuclear Physics Department annual report

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-07-01

    This annual report presents articles and abstracts published in foreign journals, covering the following subjects: nuclear structure, nuclear reactions, applied physics, instrumentation, nonlinear phenomena and high energy physics

  8. The Medicare Annual Wellness Visit.

    Science.gov (United States)

    Colburn, Jessica L; Nothelle, Stephanie

    2018-02-01

    The Medicare Annual Wellness Visit is an annual preventive health benefit, which was created in 2011 as part of the Patient Protection and Affordable Care Act. The visit provides an opportunity for clinicians to review preventive health recommendations and screen for geriatric syndromes. In this article, the authors review the requirements of the Annual Wellness Visit, discuss ways to use the Annual Wellness Visit to improve the care of geriatric patients, and provide suggestions for how to incorporate this benefit into a busy clinic. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Acquisition Workforce Annual Report 2006

    Data.gov (United States)

    General Services Administration — This is the Federal Acquisition Institute's (FAI's) Annual demographic report on the Federal acquisition workforce, showing trends by occupational series, employment...

  10. Acquisition Workforce Annual Report 2008

    Data.gov (United States)

    General Services Administration — This is the Federal Acquisition Institute's (FAI's) Annual demographic report on the Federal acquisition workforce, showing trends by occupational series, employment...

  11. [Progress on matrix metalloproteinase inhibitors].

    Science.gov (United States)

    Lingling, Jia; Qianbing, Wan

    2017-04-01

    Continuing advances in dentin bonding technology and adhesives revolutionized bonding of resin-based composite restorations. However, hybrid layers created by contemporary dentin adhesives present imperfect durability, and degradation of collagen matrix by endogenous enzymes is a significant factor causing destruction of hybrid layers. Bond durability can be improved by using enzyme inhibitors to prevent collagen degradation and to preserve integrity of collagen matrix. This review summarizes progress on matrix metalloproteinase inhibitors (including chlorhexidine, ethylenediaminetetraacetic acid, quaternary ammonium salt, tetracycline and its derivatives, hydroxamic acid inhibitors, bisphosphonate derivative, and cross-linking agents) and suggests prospects for these compounds.

  12. Uranium Industry Annual, 1992

    Energy Technology Data Exchange (ETDEWEB)

    1993-10-28

    The Uranium Industry Annual provides current statistical data on the US uranium industry for the Congress, Federal and State agencies, the uranium and electric utility industries, and the public. The feature article, ``Decommissioning of US Conventional Uranium Production Centers,`` is included. Data on uranium raw materials activities including exploration activities and expenditures, resources and reserves, mine production of uranium, production of uranium concentrate, and industry employment are presented in Chapter 1. Data on uranium marketing activities including domestic uranium purchases, commitments by utilities, procurement arrangements, uranium imports under purchase contracts and exports, deliveries to enrichment suppliers, inventories, secondary market activities, utility market requirements, and uranium for sale by domestic suppliers are presented in Chapter 2.

  13. DANSYNC. Annual report 1996

    Energy Technology Data Exchange (ETDEWEB)

    Als-Nielsen, J.

    1997-02-01

    DANSYNC is an organisation of Danish users of hard X-ray synchrotron facilities, funded by The Danish Natural Science Research Council. It was founded in the beginning of 1996, and this is the first Annual Report from DANSYNC. Users span from basic physics at Risoe National Laboratory, Oersted Laboratory and Denmarks Technical University over materials science from Risoe National Laboratory to chemistry and biology at Aarhus University, Copenhagen University and Denmarks Technical University, as well as industrial research represented by Haldor Topsoee A/S and space research at Danish Space Research Institute. We do not have an X-ray synchrotron facility in Denmark, so all of this work is carried out at facilities abroad. Clearly the facility at DESY in Hamburg (HASYLAB and EMBL) is of the greatest significance for Danish synchrotron research. Home page: http://www.dansync.dk/dansync/. (LN).

  14. Nagra annual report 2007

    Energy Technology Data Exchange (ETDEWEB)

    Ammann, M. (ed.)

    2008-07-01

    This annual report issued by the Swiss National Cooperative for the Disposal of Radioactive Waste reviews the co-operative's activities in the year 2007 and presents an overview of developments in energy policy, planning procedures and funding plans. The selection of sites for the disposal of radioactive wastes in Switzerland is discussed. Various technical questions are briefly addressed and work being carried out in the rock laboratories in the Swiss Alps and Jura mountains is discussed. International co-operation is reviewed and public relations issues are discussed. Finally, organisational structures are described and the financial details for the year 2007 are presented. The report is completed with an appendix containing the co-operative's organigram, waste inventories and listings of publications, addresses and a short glossary.

  15. Nagra annual report 2008

    Energy Technology Data Exchange (ETDEWEB)

    Ammann, M. (ed.)

    2009-07-01

    This annual report issued by the Swiss National Co-operative for the Disposal of Radioactive Waste, Nagra, reviews the co-operative's activities in the year 2008 and presents an overview of developments in energy policy, planning procedures and funding plans. Energy policy and the selection of sites for the disposal of radioactive wastes in Switzerland are discussed. Various technical questions are briefly addressed and work being carried out in the rock laboratories in the Swiss Alps and Jura mountains is discussed. International co-operation is reviewed and public relations issues are discussed. Finally, organisational structures are described and Nagra's financial details for the year 2008 are presented and discussed. The report is completed with an appendix containing the co-operative's organigram, waste inventories and listings of publications, addresses and a short glossary.

  16. Coal industry annual 1993

    Energy Technology Data Exchange (ETDEWEB)

    1994-12-06

    Coal Industry Annual 1993 replaces the publication Coal Production (DOE/FIA-0125). This report presents additional tables and expanded versions of tables previously presented in Coal Production, including production, number of mines, Productivity, employment, productive capacity, and recoverable reserves. This report also presents data on coal consumption, coal distribution, coal stocks, coal prices, coal quality, and emissions for a wide audience including the Congress, Federal and State agencies, the coal industry, and the general public. In addition, Appendix A contains a compilation of coal statistics for the major coal-producing States. This report does not include coal consumption data for nonutility Power Producers who are not in the manufacturing, agriculture, mining, construction, or commercial sectors. This consumption is estimated to be 5 million short tons in 1993.

  17. Annual energy review 1994

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-07-01

    This 13th edition presents the Energy Information Administration`s historical energy statistics. For most series, statistics are given for every year from 1949 through 1994; thus, this report is well-suited to long-term trend analyses. It covers all major energy activities, including consumption, production, trade, stocks, and prices for all major energy commodities, including fossil fuels and electricity. Statistics on renewable energy sources are also included: this year, for the first time, usage of renewables by other consumers as well as by electric utilities is included. Also new is a two-part, comprehensive presentation of data on petroleum products supplied by sector for 1949 through 1994. Data from electric utilities and nonutilities are integrated as ``electric power industry`` data; nonutility power gross generation are presented for the first time. One section presents international statistics (for more detail see EIA`s International Energy Annual).

  18. Uranium industry annual 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-04-01

    The Uranium Industry Annual 1996 (UIA 1996) provides current statistical data on the US uranium industry`s activities relating to uranium raw materials and uranium marketing. The UIA 1996 is prepared for use by the Congress, Federal and State agencies, the uranium and nuclear electric utility industries, and the public. Data on uranium raw materials activities for 1987 through 1996 including exploration activities and expenditures, EIA-estimated reserves, mine production of uranium, production of uranium concentrate, and industry employment are presented in Chapter 1. Data on uranium marketing activities for 1994 through 2006, including purchases of uranium and enrichment services, enrichment feed deliveries, uranium fuel assemblies, filled and unfilled market requirements, uranium imports and exports, and uranium inventories are shown in Chapter 2. A feature article, The Role of Thorium in Nuclear Energy, is included. 24 figs., 56 tabs.

  19. 1994 MCAP annual report

    Energy Technology Data Exchange (ETDEWEB)

    Harmony, S.C.; Boyack, B.E.

    1995-04-01

    VELCOR is an integrated, engineering-level computer code that models the progression of severe accidents in light water reactor (LWR) nuclear power plants. The entire spectrum of severe accident phenomena, including reactor coolant system and containment thermal-hydraulic response, core heatup, degradation and relocation, and fission product release and transport is treated in MELCOR in a unified framework for both boiling water reactors (BWRs) and pressurized water reactors (PWRs). Its current uses include the estimation of severe accident source terms and their sensitivities and uncertainties in a variety of applications. Independent assessment efforts have been successfully completed by the US and international MELCOR user communities. Most of these independent assessment efforts have been conducted to support the needs and fulfill the requirements of the individual user organizations. The resources required to perform an extensive set of model and integral code assessments are large. A prudent approach to fostering code development and maturation is to coordinate the individual assessment efforts of the MELCOR user community. While retaining individual control over assessment resources, each organization using the MELCOR code could work with the other users to broaden assessment coverage and minimize duplication. In recognition of these considerations, the US Nuclear Regulatory Commission (US NRC) has initiated the MELCOR Cooperative Assessment Program (MCAP), a vehicle for coordinating and standardizing the assessment practices of the various MELCOR users. In addition, the user community will have a forum to better communicate lessons learned regarding MELCOR applications, capabilities, and user guidelines and limitations and to provide a user community perspective on code development needs and priorities. This second Annual Report builds on the foundation laid with the first Annual Report.

  20. Angiogenesis Inhibitors in NSCLC

    Directory of Open Access Journals (Sweden)

    Anna Manzo

    2017-09-01

    Full Text Available Angiogenesis is a complex biological process that plays a relevant role in sustaining the microenvironment, growth, and metastatic potential of several tumors, including non-small cell lung cancer (NSCLC. Bevacizumab was the first angiogenesis inhibitor approved for the treatment of patients with advanced NSCLC in combination with chemotherapy; however, it was limited to patients with non-squamous histology and first-line setting. Approval was based on the results of two phase III trials (ECOG4599 and AVAIL that demonstrated an improvement of about two months in progression-free survival (PFS in both trials, and in the ECOG4599 trial, an improvement in overall survival (OS also. Afterwards, other antiangiogenic agents, including sunitinib, sorafenib, and vandetanib have been unsuccessfully tested in first and successive lines. Recently, two new antiangiogenic agents (ramucirumab and nintedanib produced a significant survival benefit in second-line setting. In the REVEL study, ramucirumab plus docetaxel prolonged the median OS of patients with any histology NSCLC when compared with docetaxel alone (10.4 versus 9.1 months, hazard ratio (HR 0.857, p = 0.0235. In the LUME-Lung 1 study, nintedanib plus docetaxel prolonged the median PFS of patients with any tumor histology (p = 0.0019, and improved OS (12.6 versus 10.3 months in patients with adenocarcinoma. As a result, it became a new option for the second-line treatment of patients with advanced NSCLC and adenocarcinoma histology. Identifying predictive biomarkers to optimize the benefit of antiangiogenic drugs remains an ongoing challenge.

  1. Thrombin inhibitors from different animals.

    Science.gov (United States)

    Tanaka-Azevedo, A M; Morais-Zani, K; Torquato, R J S; Tanaka, A S

    2010-01-01

    Venous and arterial thromboembolic diseases are still the most frequent causes of death and disability in high-income countries. Clinical anticoagulants are inhibitors of enzymes involved in the coagulation pathway, such as thrombin and factor X(a). Thrombin is a key enzyme of blood coagulation system, activating the platelets, converting the fibrinogen to the fibrin net, and amplifying its self-generation by the activation of factors V, VIII, and XI. Thrombin has long been a target for the development of oral anticoagulants. Furthermore, selective inhibitors of thrombin represent a new class of antithrombotic agents. For these reasons, a number of specific thrombin inhibitors are under evaluation for possible use as antithrombotic drugs. This paper summarizes old and new interests of specific thrombin inhibitors described in different animals.

  2. Thrombin Inhibitors from Different Animals

    Directory of Open Access Journals (Sweden)

    A. M. Tanaka-Azevedo

    2010-01-01

    Full Text Available Venous and arterial thromboembolic diseases are still the most frequent causes of death and disability in high-income countries. Clinical anticoagulants are inhibitors of enzymes involved in the coagulation pathway, such as thrombin and factor Xa. Thrombin is a key enzyme of blood coagulation system, activating the platelets, converting the fibrinogen to the fibrin net, and amplifying its self-generation by the activation of factors V, VIII, and XI. Thrombin has long been a target for the development of oral anticoagulants. Furthermore, selective inhibitors of thrombin represent a new class of antithrombotic agents. For these reasons, a number of specific thrombin inhibitors are under evaluation for possible use as antithrombotic drugs. This paper summarizes old and new interests of specific thrombin inhibitors described in different animals.

  3. Selective Serotonin Reuptake Inhibitors (SSRIs)

    Science.gov (United States)

    ... Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects. http://www.uptodate.com/home. Accessed June 2, 2016. Mental health medications. National Institute of Mental Health. http://www. ...

  4. Formulary management of ACE inhibitors.

    Science.gov (United States)

    Gerbrandt, K R; Yedinak, K C

    1996-12-01

    An increasing number of ACE inhibitors have become available in recent years. Because these agents are all similar, careful scrutiny is required in order to determine specific advantages of particular agents when making formulary decisions. Differences between agents with regard to structure and tissue specificity have been identified, but the clinical relevance of these differences is not clear. ACE inhibitors vary greatly with regard to bioconversion, distribution and elimination. Disease states such as congestive heart failure (CHF) and hepatic or renal insufficiency may affect the disposition of specific ACE inhibitors. These agents may differ substantially in duration of action, and ACE inhibitors that are given once daily may optimise patient compliance and decrease costs. ACE inhibitors have been extensively studied in patients with hypertension, CHF or nephropathy, and following myocardial infarction (MI). Differences in efficacy between agents are often a result of variations in study design, or because nonequipotent dosages were compared. It is likely that the benefits of ACE inhibitors are class effects, and it is probably reasonable to use an agent even if large scale clinical trials have not been performed with that particular drug. Few differences have been found between ACE inhibitors with regard to adverse effects or drug interactions, and these factors are of minor importance when making formulary decisions. Cost and availability may vary among agents, and will depend on geographical location and institution-specific purchasing contracts. ACE inhibitors have shown positive effects on quality of life when compared with agents of other classes. Quality-of-life studies that have directly compared ACE inhibitors have produced conflicting results. In the setting of hypertension, cost-effectiveness evaluations typically find that the newer, longer-acting ACE inhibitors provide the greatest financial benefit. Differences in cost effectiveness in the post

  5. Advantages of the WRAIR whole blood cholinesterase assay: comparative analysis to the micro-Ellman, Test-mate ChE, and Michel (DeltapH) assays.

    Science.gov (United States)

    Haigh, Julian R; Lefkowitz, Lee J; Capacio, Benedict R; Doctor, Bhupendra P; Gordon, Richard K

    2008-09-25

    Red blood cell AChE (RBC-AChE) and plasma BChE can be used as sensitive biomarkers to detect exposure to OP nerve agents, pesticides, and cholinergic drugs. In a comparative study, RBC-AChE and serum BChE activities in whole blood was obtained from forty seven healthy male and female human volunteers, and then exposed separately ex vivo to three OP nerve agents (soman (GD), sarin (GB) and VX) to generate a wide range of inhibition of AChE and BChE activity (up to 90% of control). These samples were measured using four different ChE assays: (i) colorimetric microEllman (using DTNB at 412 nm), (ii) Test-mate ChE field kit (also based on the Ellman assay), (iii) Michel (delta pH), and (iv) the Walter Reed Army Institute of Research Whole Blood (WRAIR WB) cholinesterase assay. The WRAIR assay is a modified Ellman method using DTP at 324 nm (which minimizes hemoglobin interference and improves sensitivity), and determines AChE and BChE in a small whole blood sample simultaneously. Scatter plots of RBC-AChE activities were determined using the WRAIR ChE assay versus the micro-Ellman, Test-mate and Michel after exposure to varying concentrations of soman, sarin and VX. Regression analyses yielded mostly linear relationships with high correlations (r2 = 0.83-0.93) for RBC-AChE values in the WRAIR assay compared to the alternate methods. For the plasma BChE measurements, individual human values were significantly more variable (as expected), resulting in lower correlations using WRAIR ChE versus the alternate assays (r2 values 0.5 - 0.6). To circumvent the limitations of simple correlation analysis, Bland and Altman analysis for comparing two independent measurement techniques was performed. For example, a Bland and Altman plot of the ratio of the WRAIR whole blood AChE and Michel AChE (plotted on the y-axis) vs. the average of the two methods (x-axis) shows that the majority of the individual AChE values are within +/- 1.96 S.D. of the mean difference, indicating that the

  6. SKB Annual Report 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-05-01

    This is the annual report of the Swedish Nuclear Fuel and Waste Management Co (SKB). Part 1 of the report contains an overview of the SKB activities in different fields, and part 2 gives a description of the research and development work on nuclear waste disposal performed during 1996. Lectures and publications as well as reports issued during 1996 are listed in part 3, and summaries of the reports are listed in part 4. The task of SKB is to transport, store and dispose of the spent nuclear fuel and radioactive wastes from the nuclear power plants and to perform the research and development and other measures necessary for this work. SKB is the owner of CLAB, the Central Interim Storage Facility for spent fuel, located at Oskarshamn. CLAB was taken into operation in July 1985 and by the end of 1996 about 2500 tons of spent fuel have been received. At Forsmark the Final Repository for Radioactive Operational Waste (SFR) was taken into operation in April 1988. The repository is situated in crystalline rock under the Baltic Sea. SFR has currently a capacity of about 60000 m{sup 3} or waste. At the end of 1996 at total of 21000 m{sup 3} of waste has been deposited. Transportation from the reactor sites to CLAB and SFR is made by a specially designed ship, M/S Sigyn. The total cost for R,D and D during 1996 amounted to 124 MSEK (about 15 MUSD).

  7. Annual Report 1998

    Energy Technology Data Exchange (ETDEWEB)

    Chmielewska, D.; Infeld, E.; Preibisz, Z.; Zupranski, P. [eds.

    1999-10-01

    In the presented ``Annual Report 1998`` the scientific, organizational and educational activities of the Andrzej Soltan Institute for Nuclear Studies (SINS) are presented. The document is divided into two parts. First of them consists of the general information about management, scientific council, department of SINS, scientific staff, visiting scientists, list of research project (grants), PhD and DSc theses as well as the information about organized schools and exhibitions. The second one: ``Reports on Research`` describes the research activities of SINS. It is divided into 12 parts - in which the works of SINS departments and establishments are presented (Department of Nuclear Reactions, Department of Nuclear Spectroscopy and Technique, Department of Nuclear Electronics, Department of Radiation Shielding and Dosimetry, Department of Plasma Physics and Technology, Department of High Energy Physics, Department of Cosmic Radiation Physics, Department of Nuclear Theory, Department of Radiation Detectors, Department of Accelerator Physics and Technology, Department of Training an Consulting and Establishment for Nuclear Equipment). Each of these parts are preceded by a short overview given by the head of the given department. The foreword, in which the whole activities of the SINS are summarized, given by head of the Institute professor Z. Sujkowski is also given

  8. Annual Energy Review 2002

    Energy Technology Data Exchange (ETDEWEB)

    Seiferlein, Katherine E. [USDOE Energy Information Administration (EIA), Washington, DC (United States)

    2003-10-01

    The Annual Energy Review (AER) presents the Energy Information Administration’s historical energy statistics. For many series, statistics are given for every year from 1949 through 2002. The statistics, expressed in either physical units or British thermal units, cover all major energy activities, including consumption, production, trade, stocks, and prices, for all major energy commodities, including fossil fuels, electricity, and renewable energy sources. Publication of this report is required under Public Law 95–91 (Department of Energy Organization Act), Section 205(c), and is in keeping with responsibilities given to the Energy Information Administration (EIA) under Section 205(a)(2), which states: “The Administrator shall be responsible for carrying out a central, comprehensive, and unified energy data and information program which will collect, evaluate, assemble, analyze, and disseminate data and information....” The AER is intended for use by Members of Congress, Federal and State agencies, energy analysts, and the general public. EIA welcomes suggestions from readers regarding data series in the AER and in other EIA publications. Related Publication: Readers of the AER may also be interested in EIA’s Monthly Energy Review, which presents monthly updates of many of the data in the AER. Contact our National Energy Information Center for more information.

  9. Annual Energy Review 2000

    Energy Technology Data Exchange (ETDEWEB)

    Seiferlein, Katherine E. [USDOE Energy Information Administration (EIA), Washington, DC (United States)

    2001-08-01

    The Annual Energy Review (AER) presents the Energy Information Administration’s historical energy statistics. For many series, statistics are given for every year from 1949 through 2000. The statistics, expressed in either physical units or British thermal units, cover all major energy activities, including consumption, production, trade, stocks, and prices, for all major energy commodities, including fossil fuels, electricity, and renewable energy sources. Publication of this report is required under Public Law 95–91 (Department of Energy Organization Act), Section 205(c), and is in keeping with responsibilities given to the Energy Information Administration under Section 205(a)(2), which states: “The Administrator shall be responsible for carrying out a central, comprehensive, and unified energy data and information program which will collect, evaluate, assemble, analyze, and disseminate data and information....” The AER is intended for use by Members of Congress, Federal and State agencies, energy analysts, and the general public. EIA welcomes suggestions from readers regarding data series in the AER and in other EIA publications.

  10. Annual report 1997

    Energy Technology Data Exchange (ETDEWEB)

    Chmielewska, D.; Infeld, E.; Zupranski, P. [eds.

    1998-12-31

    In the presented ``Annual Report 1997`` the scientific, organizational end educational activities of the Andrzej Soltan Institute for Nuclear Studies (SINS) are presented. The document is divided into two parts. First of them consist of the general information about management, scientific council, department of SINS, scientific staff, visiting scientists, list of research project (grants), PhD and DSc theses as well as the information about organized schools and exhibitions. The second one: ``Reports on Research`` describes the research activities of SINS. It is divided into 12 parts - in which the works of SINS departments and establishments are presented (Department of Nuclear Reactions, Department of Nuclear Spectroscopy and Technique, Department of Nuclear Electronics, Department of Radiation Shielding and Dosimetry, Department of Plasma Physics and Technology, Department of High Energy Physics, Department of Cosmic Radiation Physics, Department of Atomic Nucleus Theory, Department of Radiation Detectors, Department of Accelerator Physics and Technology, Department of Training an Consulting and Establishment for Nuclear Equipment). Each of these parts are foreworded by short overview given by the head of appropriate department. The foreword, in which the whole activities of the SINS are summarized, given by head of the Institute professor Z. Sujkowski is also given

  11. ANNUAL INTERVIEWS (MAPS)

    CERN Multimedia

    Human Resources Division

    2002-01-01

    The calendar for the 2002/2003 annual interview programme is confirmed as normally from 15 November 2002 to 15 February 2002 as foreseen in Administrative Circular N° 26 (rev. 2). However, where it is preferred to be as close as possible to 12 months since the last interview, supervisors and staff concerned may agree to the interview taking place up to 15 March 2003. This may also be necessary due to the roles of different supervisors resulting from the particular situations of divisional re-restructurings and detachments this year. The report form template is as last year available on the HR Division Website. A banner on the internal homepage leads directly to the page with the form. In collaboration with AS Division, the MAPS form including the personal data for the first page can be generated via the Human Resources Toolkit (HRT) application. For this exercise each staff member can now generate his/her own MAPS form. Information about how to do this is available here. Human Resources Division Tel. ...

  12. 2007 LDRD ANNUAL REPORT

    Energy Technology Data Exchange (ETDEWEB)

    French, T

    2008-12-16

    I am pleased to present the fiscal year 2007 Laboratory Directed Research and Development (LDRD) annual report. This represents the first year that SRNL has been eligible for LDRD participation and our results to date demonstrate we are off to an excellent start. SRNL became a National Laboratory in 2004, and was designated the 'Corporate Laboratory' for the DOE Office of Environmental Management (EM) in 2006. As you will see, we have made great progress since these designations. The LDRD program is one of the tools SRNL is using to enable achievement of our strategic goals for the DOE. The LDRD program allows the laboratory to blend a strong basic science component into our applied technical portfolio. This blending of science with applied technology provides opportunities for our scientists to strengthen our capabilities and delivery. The LDRD program is vital to help SRNL attract and retain leading scientists and engineers who will help build SRNL's future and achieve DOE mission objectives. This program has stimulated our research staff creativity, while realizing benefits from their participation. This investment will yield long term dividends to the DOE in its Environmental Management, Energy, and National Security missions.

  13. Annual conference SAEE 2008

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2008-07-01

    Technical and economic challenges of a 1 t CO{sub 2} society was the topic addressed by the 2008 annual conference of the Swiss Association for Energy Economics. One tonne of carbon dioxide per head and year as a long-term energy strategy is the theme of a presentation made by professor Konstantin Boulouchos from the Swiss Federal Institute of Technology ETH in Zurich, Switzerland. Professor Dr. Rainhard Madlener from the Institute for Future Energy Consumer Needs and Behaviour in Aachen, Germany, took a look at the one-ton CO{sub 2} vision as a focus for technical development. Professor Thomas F. Rutherford from the ETH presented an economic analysis of one-ton CO{sub 2} scenarios. Eduard Schumacher, former Chairman of the Board at the IWB utility in Basel, Switzerland, presented examples of how energy policy can be implemented, using the IWB's activities as an example. Hansruedi Kunz, Head of the Energy Department in the Building Department of the Canton of Zurich discussed the chances offered and the problems posed by the implementation of measures that are to lead to the meeting of energy visions for the year 2050. A podium and discussion session completed the conference

  14. Annual Energy Review 1997

    Energy Technology Data Exchange (ETDEWEB)

    Seiferlein, Katherine E. [USDOE Energy Information Administration (EIA), Washington, DC (United States)

    1998-07-01

    The Annual Energy Review (AER) presents the Energy Information Administration’s historical energy statistics. For many series, statistics are given for every year from 1949 through 1997. The statistics, expressed in either physical units or British thermal units, cover all major energy activities, including consumption, production, trade, stocks, and prices, for all major energy commodities, including fossil fuels, electricity, and renewable energy sources. Publication of this report is in keeping with responsibilities given to the Energy Information Administration (EIA) in Public Law 95–91 (Department of Energy Organization Act), which states, in part, in Section 205(a)(2) that: “The Administrator shall be responsible for carrying out a central, comprehensive, and unified energy data and information program which will collect, evaluate, assemble, analyze, and disseminate data and information....” The AER is intended for use by Members of Congress, Federal and State agencies, energy analysts, and the general public. EIA welcomes suggestions from readers regarding data series in the AER and in other EIA publications.

  15. 2014 HPC Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    Jennings, Barbara [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2014-10-01

    Our commitment is to support you through delivery of an IT environment that provides mission value by transforming the way you use, protect, and access information. We approach this through technical innovation, risk management, and relationships with our workforce, Laboratories leadership, and policy makers nationwide. This second edition of our HPC Annual Report continues our commitment to communicate the details and impact of Sandia’s large-scale computing resources that support the programs associated with our diverse mission areas. A key tenet to our approach is to work with our mission partners to understand and anticipate their requirements and formulate an investment strategy that is aligned with those Laboratories priorities. In doing this, our investments include not only expanding the resources available for scientific computing and modeling and simulation, but also acquiring large-scale systems for data analytics, cloud computing, and Emulytics. We are also investigating new computer architectures in our advanced systems test bed to guide future platform designs and prepare for changes in our code development models. Our initial investments in large-scale institutional platforms that are optimized for Informatics and Emulytics work are serving a diverse customer base. We anticipate continued growth and expansion of these resources in the coming years as the use of these analytic techniques expands across our mission space. If your program could benefit from an investment in innovative systems, please work through your Program Management Unit ’s Mission Computing Council representatives to engage our teams.

  16. Design, synthesis and biological evaluation of dual acetylcholinesterase and phosphodiesterase 5A inhibitors in treatment for Alzheimer's disease.

    Science.gov (United States)

    Zhou, Li-Yun; Zhu, Yao; Jiang, Yu-Ren; Zhao, Xiong-Jie; Guo, Dong

    2017-09-01

    With the recent research advances in molecular biology and technology, multiple credible hypotheses about the progress of Alzheimer's disease (AD) have been proposed; multi-target drugs have emerged as an innovative therapeutic approach for AD. Current clinical therapy for AD patients is mainly palliative treatment targeting acetylcholinesterase (AChE). Inhibition of phosphodiesterase 5A (PDE5A) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). In this work, series of new compounds were designed, synthesized and evaluated as dual cholinesterase and PDE5A inhibitor. Biological results revealed that some of these compounds display good biological activities against AChE with IC50 values about 44.67-169.80nM (donepezil IC50 50.12nM). Notably, compound 12 presented potent activities against PDE5A with IC50 values about 50μM (sildenafil IC50 12.59μM), and some of these compounds showed low cell toxicity to A549 cells in vitro. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Preliminary findings of the effects of rivastigmine, an acetylcholinesterase inhibitor, on working memory in cocaine-dependent volunteers.

    Science.gov (United States)

    Mahoney, James J; Kalechstein, Ari D; Verrico, Christopher D; Arnoudse, Nicholas M; Shapiro, Benjamin A; De La Garza, Richard

    2014-04-03

    Long-term cocaine use is a risk factor for the onset of neurocognitive impairment. This study sought to determine whether the cholinesterase inhibitor rivastigmine could improve neurocognitive performance in cocaine-dependent individuals. Cocaine-dependent individuals who were not seeking treatment at the time of enrollment in the study were randomly assigned to receive placebo (n=16), rivastigmine 3mg (n=13), or rivastigmine 6mg (n=12). The baseline neurocognitive assessment, which included measures of attention/information processing (as measured by the Continuous Performance Task-II (CPT-II)), verbal learning/episodic memory (as measured by the Hopkins Verbal Learning Test-Revised (HVLT-R)), and working memory (as measured by the Dual N-Back Task), was conducted prior to the administration of study medication (Day 0). The follow-up assessment was conducted on Day 8 after the participants had received rivastigmine or placebo for 7days (Day 2-8). Rivastigmine administration significantly improved performance on one measure of working memory span (mean n-back span). This study provides additional data showing that cocaine-associated neurocognitive impairment, specifically working memory deficits, can be remediated, at least to some degree. Copyright © 2013. Published by Elsevier Inc.

  18. 2005 Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    Chrzanowski, P; Walter, K

    2006-03-31

    As the cover of our ''2005 Annual Report'' highlights, Lawrence Livermore National Laboratory joined the international science community in celebrating the World Year of Physics in 2005, with special events and science outreach and education programs. Einstein's remarkable discoveries in 1905 provided an opportunity to reflect on how physics has changed the world during the last century and on the promise of future beneficial discoveries. For half of the past century, Lawrence Livermore, which was established to meet an urgent national security need, has been contributing to the advancement of science and technology in a very special way. Co-founder Ernest O. Lawrence was the leading proponent in his generation of large-scale, multidisciplinary science and technology teams. That's Livermore's distinctive heritage and our continuing approach as a national laboratory managed and operated by the University of California for the Department of Energy's National Nuclear Security Administration (DOE/NNSA). We focus on important problems that affect our nation's security and seek breakthrough advances in science and technology to achieve mission goals. An event in 2005 exemplifies our focus on science and technology advances in support of mission goals. In October, distinguished visitors came to Livermore to celebrate the tenth anniversary of the Accelerated Strategic Computing Initiative (now called the Advanced Simulation and Computing Program, or ASC). ASC was launched in 1995 by DOE/NNSA to achieve a million-fold increase in computing power in a decade. The goal was motivated by the need to simulate the three-dimensional performance of a nuclear weapon in sufficient resolution and with the appropriately detailed physics models included. This mission-driven goal is a key part of fulfilling Livermore's foremost responsibility to ensure that the nuclear weapons in the nation's smaller 21st-century stockpile remain

  19. Annual energy review 2003

    Energy Technology Data Exchange (ETDEWEB)

    Seiferlein, Katherin E. [Energy Information Adminstration (EIA), Washington, DC (United States)

    2004-09-30

    The Annual Energy Review 2003 is a statistical history of energy activities in the United States in modern times. Data are presented for all major forms of energy by production (extraction of energy from the earth, water, and other parts of the environment), consumption by end-user sector, trade with other nations, storage changes, and pricing. Much of the data provided covers the fossil fuels—coal, petroleum, and natural gas. Fossil fuels are nature’s batteries; they have stored the sun’s energy over millennia past. It is primarily that captured energy that we are drawing on today to fuel the activities of the modern economy. Data in this report measure the extraordinary expansion of our use of fossil fuels from 29 quadrillion British thermal units (Btu) in 1949 to 84 quadrillion Btu in 2003. In recent years, fossil fuels accounted for 86 percent of all energy consumed in the United States. This report also records the development of an entirely new energy industry—the nuclear electric power industry. The industry got its start in this country in 1957 when the Shippingport, Pennsylvania, nuclear electric power plant came on line. Since that time, the industry has grown to account for 20 percent of our electrical output and 8 percent of all energy used in the country. Renewable energy is a third major category of energy reported in this volume. Unlike fossil fuels, which are finite in supply, renewable energy is essentially inexhaustible because it can be replenished. Types of energy covered in the renewable category include conventional hydroelectric power, which is power derived from falling water; wood; waste; alcohol fuels; geothermal; solar; and wind. Together, these forms of energy accounted for about 6 percent of all U.S. energy consumption in recent years.

  20. Annual Report, 1998

    Energy Technology Data Exchange (ETDEWEB)

    Buettner, Herma G.; Leadbetter, Alan J. [eds.] [Institut Max von Laue - Paul Langevin (ILL), 38 - Grenoble (France)

    1999-11-01

    In this Annual Report a selection of about 30 scientific achievements are highlighted. These are intended to represent the huge range of high quality research carried out at ILL. In 1998 about 750 experiments were performed in the 225 days of reactor operation. The fields of magnetism and strongly correlated electron systems continue to be fertile and to throw up strong new growth. Remarkable new advances are coming from the applications of both existing and new neutron techniques and the development of new materials. These highlights concern superconductors, nano-magnetic particles, colossal magneto-resistance, magnetic-nuclear correlations, quantum spin systems and more. Novel magnetic measurements are also reported for a quasicrystal and on thin films of both normal and superconducting materials. Thanks to special abilities of neutrons to penetrate matter new results were obtained: following the production of novel intermetallic compounds, pressure dependence of phonon frequencies, the structure of glasses, solutions (in both bulk and thin films) and adsorbed phases; dynamics and relaxation in liquids; the confirmation of reptant motion in linear polymers, self-assembly and shear phenomena in liquid crystals. Three important results from nuclear physics are also included. These involve: fission-produced neutron-rich nuclei, weighing gamma photons in connection with the determination of fundamental constants and the determination of interatomic potentials from the slowing down process of atoms recoiling from gamma-ray emission - a direct link between nuclear and solid-state physics. The neutron experiments of importance for particle physics and biology will be reported next year

  1. 1998 annual review

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1999-05-01

    The Canadian Petroleum Products Institute (CPPI) is an association of Canadian companies involved in the refining, distribution and marketing of petroleum products. CPPI`s responsibilities include (1) establishing environmental policies, (2) establishing working relationships with governments to develop public policy, (3) developing guidelines for the safe handling of petroleum products, and (4) providing information about the petroleum industry to the public. This annual review summarizes industry operations and trends within the crude oil and petroleum products industry. In 1998, Canada`s 19 CPPI member refineries processed an average of 1.6 million barrels of crude oil per day. The CPPI developed a policy position on climate change and continued its strong support of the Canadian Voluntary Challenge and Registry Program. It initiated a major consumer information campaign regarding gasoline prices. It held a pollution prevention workshop to discuss issues related to air, land and water quality. It launched a website (www.cppi.ca) as another mechanism to provide its audience with information about the industry. Across Canada, CPPI`s regional offices supported a number of industry initiatives, such as the work in Dartmouth, NS, on a Risk-based Correction Action process for the clean-up of sites contaminated with petroleum products, discussions on the development of a used oil program for Quebec, regulatory reform in Ontario, and support by the Calgary office in the implementation of used oil recycling programs in the Prairies. CPPI also participated in discussions concerning the establishment of standards regarding sulphur and benzene in gasoline, and the future regarding the octane enhancing fuel additive MMT for transportation fuels. It was also reported that CPPI members are on track towards achieving a 65 per cent reduction in refinery benzene emissions between 1993 and 2000. tabs., figs.

  2. Annual energy review 1997

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-07-01

    The Annual Energy Review (AER) is a historical data report that tells many stories. It describes, in numbers, the changes that have occurred in US energy markets since the midpoint of the 20th century. In many cases, those markets differ vastly from those of a half-century ago. By studying the graphs and data tables presented in this report, readers can learn about past energy supply and usage in the United States and gain an understanding of the issues in energy and the environment now before use. While most of this year`s report content is similar to last year`s, there are some noteworthy developments. Table 1.1 has been restructured into more summarized groupings -- fossil fuels, nuclear electric power, and renewable energy -- to aid analysts in their examination of the basic trends in those broad categories. Readers` attention is also directed to the electricity section, where considerable reformatting of the tables and graphs has been carried out to help clarify past and recent trends in the electric power industry as it enters a period of radical restructuring. Table 9.1, which summarizes US nuclear generating units, has been redeveloped to cover the entire history of the industry in this country and to provide categories relevant in assessing the future of the industry, such as the numbers of ordered generating units that have been canceled and those that were built and later shut down. In general, the AER emphasizes domestic energy statistics. Sections 1 through 10 and Section 12 are devoted mostly to US data; Section 11 reports on international statistics and world totals. 140 figs., 141 tabs.

  3. Positron emitter labeled enzyme inhibitors

    Science.gov (United States)

    Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.

    1987-05-22

    This invention involved a new strategy for imaging and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide in activators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography. 2 figs.

  4. PROTEIN INHIBITORS SYNTHESISED BY MICROORGANISMS

    Directory of Open Access Journals (Sweden)

    O. V. Matseliukh

    2013-12-01

    Full Text Available In a review the literature data on protein inhibitors of peptidases synthesised by different types of microorganisms are systematized. It is shown that at the present time on the basis of amino acid sequence homology protein inhibitors are grouped into 77 families, 29 of which include inhibitors of microorganisms. The mechanism of inhibition of peptidases by proteins may be related to their catalytic mechanism of action or include unrelated blocking of the active site or its surroundings. The structural elements of the protein inhibitors are responsible for binding to the peptidases, mostly include the N- or C-terminal sequences, the unprotected polypeptide loops (chains, which are acting independently or in combination with other elements. The basic properties, structural features and, where it is established, the functions of the protein inhibitors of peptidases are considered. Since some of these proteins effectively inhibit such peptidases as subtilisin, chymotrypsin, pancreatic elastase, their practical use in the treatment of diseases such as emphysema, arthritis, pancreatitis, thrombosis, hypertension, muscular dystrophy, cancer. It is suggested that the role of a bacterial homologue of Escherichia coli alphaacroglobulin, which is a periplasmic protein, is to protect the periplasmic space from the action of bacteria own proteases. Based on the specific properties of alpha-2-macroglobulin to bind endopeptidases active molecules, they are used in biotechnology to isolate endopeptidases from crude biological preparations and titration of its active centers. Some free–living bacteria are able to synthesize protein inhibitors to protect from the effects of its own enzymes, while the presence of these proteins in pathogens may play a certain role both in the infectious process and in the protection of the host proteases.

  5. Nursing Facility Initiative Annual Report

    Data.gov (United States)

    U.S. Department of Health & Human Services — This annual report summarizes impacts from the Initiative to Reduce Avoidable Hospitalizations among Nursing Facility Residents in 2014. This initiative is designed...

  6. Florida annual general canvass statistics

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This data set contains annual quantities and value for all seafood products that are landed and sold by established seafood dealers and brokers in Florida. These...

  7. Isolation and structural identification of a germination inhibitor in fire-recruiters from the California chaparral.

    Science.gov (United States)

    Egerton-Warburton, L M; Ghisalberti, E L

    2001-02-01

    A role for inhibitors as regulators of seed dormancy in fire-dependent annuals and their nondormant (fire-independent) congeners was examined in the family Hydrophyllaceae. From seeds of the fire-dependent species, Emmenanthe penduliflora, Phacelia minor, P. brachyloba, and P. grandiflora, extracts were obtained that were found to be largely self-inhibitory and potent inhibitors of seed germination in nondormant congeners. Lower activity was detected in the fire-independent species, P. tanacetifolia and P. campanularia. The inhibitory activity was associated with the new sucrose ester, 6-O-linoleyl-alpha-D-glucopyranosyl-beta-D-fructofuranoside.

  8. Annual report 99

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1999-07-01

    This volume of the Annual Report for the year 1999 provides the best illustration of this attempt: 30 highlights are presented covering a remarkable range of science and technique. As with last year's report, a wide spectrum of neutron science is embraced from biology, through to studies in chemistry, materials science and magnetism, to particle physics. To maintain this excellence, important efforts have been made in instrumentation; they are described in the technical section together with the Millennium Programme. This report is an appropriate illustration of the unique value of neutron methods for the study of a wide range of materials proving the usefulness of large-scale facilities such as the ILL. In 1999, the reactor operated for 208 days and more than 700 experiments were carried out in over 4400 days of scheduled beam time. Unfortunately, there was a failure of the hot source in December 1999 leading to a loss of about 20 days of beam time. Therefore, in 2000 the reactor will operate without the hot source. However, this will only affect 10 % of ILL's instruments. As in previous years, a large number of high-quality experiments was proposed and performed to tackle a broad range of scientific questions. For example in biology, the results presented here demonstrate that the contrast-variation method combined with small-angle scattering and neutron reflectivity techniques is a remarkable and unique tool for the investigation of biological materials. In the field of soft matter and liquids, it is known that confined geometry substantially modifies the properties of systems as diverse as simple water, polymers and quantum fluids. Neutron scattering experiments, presented here, have revealed the static and dynamic characteristics of these materials under conditions of confinement. In materials sciences, the penetration and contrast properties of neutrons are exploited, particularly in the case of small-angle scattering applied to alloys. Finally, the

  9. NERI 2004 Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    None

    2004-01-01

    The United States Department of Energy (DOE) created the Nuclear Energy Research Initiative (NERI) in Fiscal Year (FY) 1999 in response to recommendations provided by the President's Committee of Advisors on Science and Technology. The purpose of NERI is to sponsor research and development (R&D) in the nuclear energy sciences to address the principal barriers to the future use of nuclear energy in the United States. NERI is helping to preserve the nuclear science and engineering infrastructure within the Nation's universities, laboratories, and industry, and is advancing the development of nuclear energy technology, enabling the United States to maintain a competitive position in nuclear science and technology. Research under this initiative also addresses issues associated with the maintenance of existing U.S. nuclear plants. The NERI program is managed and funded by DOE's Office of Nuclear Energy, Science and Technology. ''The Nuclear Energy Research Initiative 2004 Annual Report'' serves to inform interested parties of progress made in NERI on a programmatic level as well as research progress made on individual NERI projects. Section 2 of this report provides background on the creation and implementation of NERI and on the focus areas for NERI research. Section 3 provides a discussion on NERI's mission, goals and objectives, and work scope. Section 4 highlights the major accomplishments of the NERI projects and provides brief summaries of the NERI research efforts that were completed in 2004. Section 5 provides a discussion on the impact NERI has had on U.S. university nuclear programs. Sections 6 through 8 provide project status reports by research area for each of the fiscal year (FY) 2001 and 2002 projects that were active in FY 2004. Research objectives, progress made over the last year, and activities planned for the next year are described for each project. Sections 9 through 11 present each of the newly awarded 2005

  10. Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer.

    Science.gov (United States)

    Ivy, S Percy; Liu, Joyce F; Lee, Jung-Min; Matulonis, Ursula A; Kohn, Elise C

    2016-01-01

    An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC. Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts. Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.

  11. Study of the correlation between blood cholinesterases activity, urinary dialkyl phosphates, and the frequency of micronucleated polychromatic erythrocytes in rats exposed to disulfoton

    Directory of Open Access Journals (Sweden)

    Mariane Gonçalves Santos

    2013-03-01

    Full Text Available Organophosphates (OPs are widely used as pesticides, and its urinary metabolites as well as the blood cholinesterases (ChEs activity have been reported as possible biomarkers for the assessment of this pesticide exposure. Moreover, the OPs can induce mutagenesis, and the bone marrow micronucleus test is an efficient way to assess this chromosomal damage. This paper reports a study carried out to verify the correlation among the disulfoton exposure, blood ChEs activity, urinary diethyl thiophosphate (DETP, and diethyl dithiophosphate (DEDTP, as well as micronucleated polychromatic erythrocytes (MNPCEs frequency. Four groups of rats (n=12 were exposed to disulfoton at 0, 2.8, 4.7, and 6.6 mg kg-1 body weight. The blood ChEs activity, urinary DETP and DEDTP concentrations, and MNPCEs frequency were determined. It was observed that the plasmatic and erythrocytary ChEs activity decreased from 2.9% to 0.5% and from 35.9 to 3.3%, respectively, when the disulfoton dose was increased from 0 to 6.6 mg kg-1 (correlation of 0.99. Urinary DETP and DEDTP concentrations, as well as the MNPCEs frequency, increased from 0 to 6.58 µg mL-1, from 0 to 0.04 µg mL-1, and from 0 to 1.4%, respectively, when the disulfoton dose was increased from 0 to 6.58 mg kg-1 body weight.Os organofosforados (OPs são amplamente usados como praguicidas e a atividade da colinesterase sanguínea bem como os metabólitos urinários desses praguicidas têm sido reportados como biomarcadores eficazes para avaliar casos de exposição. Além disso, os OPs podem induzir mutagênese e o teste de micronúcleo de medula óssea é uma boa alternativa para avaliar os danos cromossômicos. Esse artigo reporta um estudo sobre a correlação entre a exposição a dissulfoton, a atividade da colinesterase sanguínea, a excreção urinária de dietil tiofosfato e dietil ditiofosfato e a frequência de micronúcleos em eritrócitos policromáticos. Quatro grupos de ratos (n=12 foram expostos a

  12. Proton pump inhibitors and gastroenteritis

    NARCIS (Netherlands)

    R.J. Hassing (Robert); A. Verbon (Annelies); H. de Visser (Herman); A. Hofman (Albert); B.H.Ch. Stricker (Bruno)

    2016-01-01

    textabstractAn association between proton pump inhibitor (PPI) therapy and bacterial gastroenteritis has been suggested as well as contradicted. The aim of this study was to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis in the prospective Rotterdam

  13. Nitrification inhibitor's effect on mitigating N2O emissions was weakened by urease inhibitor in calcareous soils

    Science.gov (United States)

    Zhao, Zichao; Wu, Di; Bol, Roland; Shi, Yuefeng; Guo, Yanbin; Meng, Fanqiao; Wu, Wenliang

    2017-10-01

    The application of nitrification or urease inhibitors together with nitrogen (N) fertilizer has been proposed to reduce N losses, including nitrous oxide (N2O) emissions, from agricultural soils. We measured N2O fluxes, crop yield and plant N content over 3 years (2012-2015) to evaluate the long-term effects of nitrification and/or urease inhibitors on N2O emissions, crop production and N use efficiency (NUE) in an intensively farmed wheat-maize system in northern China. The experiment consisted of the following five treatments: 1) CK, no N fertilizer; 2) U, urea; 3) NI, urea with 3,4-dimethylpyrazole phosphate (DMPP); 4) UI, urea with N-(n-butyl) thiophosphoric triamide (NBPT); and 5) NIUI, urea with combined DMPP and NBPT. Compared with the U treatment, the NI, NIUI and UI treatments mitigated cumulative N2O emissions by 55%, 40% and 21% in the maize season, respectively, and 47%, 40% and 33% in the wheat season, respectively. The annual direct emission factors of N2O for the U, NI, UI and NIUI treatments were 0.4%, 0.1%, 0.3% and 0.2%, respectively. The NIUI, NI and UI treatments increased the annual crop yield (7%, 6% and 4%) and the NUE (15%, 10% and 7%) relative to the U treatment. The NI treatment showed the best effect on mitigating N2O emissions, but its efficacy was reduced when applied together with UI. This indicates that more studies are required focusing on the performances and mechanisms of these two inhibitors in alkaline and low organic carbon soils.

  14. 78 FR 64912 - Annual Retail Trade Survey

    Science.gov (United States)

    2013-10-30

    ... survey, the Census Bureau will collect data covering annual sales, annual e-commerce sales, year-end... annual sales, annual e-commerce sales, year-end inventories held inside and outside the United States... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE...

  15. 77 FR 64463 - Annual Retail Trade Survey

    Science.gov (United States)

    2012-10-22

    ..., the Census Bureau will collect data covering annual sales, annual e- commerce sales, year-end..., accounts receivables, and, for selected industries, merchandise line sales, and percent of e-commerce sales..., annual sales, annual e-commerce sales, purchases, total and detailed operating expenses, accounts...

  16. 75 FR 63804 - Annual Retail Trade Survey

    Science.gov (United States)

    2010-10-18

    ... survey, the Census Bureau will collect data covering annual sales, annual e-commerce sales, year-end... percent of e-commerce sales to customers located outside the United States. These data are collected to... classification basis, annual sales, annual e-commerce sales, purchases, total operating expenses, accounts...

  17. Reading Ease of Bilingual Annual Reports.

    Science.gov (United States)

    Courtis, John K.; Hassan, Salleh

    2002-01-01

    Examines reading ease between the English and Chinese versions of 65 corporate annual reports in Hong Kong and the English and Malay versions of 53 annual reports in Malaysia. Notes that the English passages in Malaysian annual reports are easier to read than the English passages in Hong Kong annual reports. Suggests that different language…

  18. Tolerance of two Bifora radians bieb populations to ALS inhibitors in winter wheat

    DEFF Research Database (Denmark)

    Mennan, Husrev; Streibig, Jens Carl; Ngouajio, Mathieu

    2012-01-01

    allegedly sensitive population was estimated at the ED50 and ED90 response levels. The recommended rates of herbicides controlled 90% of the weed (ED90) in the sensitive population at the early stage of B. radians development, but not in the tolerant population. The relative potencies (EDx......BACKGROUND:Bifora radians, an annual weed in winter wheat, is distributed mainly in the Mediterranean area, Asia Minor and the Caucasus. It infests winter-sown crops of the Central Anatolia and Middle Black Sea regions of Turkey. Field experiments in heavily B. radians-infested fields were...... conducted over 3 years in Samsun, Turkey, to determine the response of B. radians to ALS-inhibiting herbicides, because growers had complained of a decrease in herbicide effect. RESULTS: The efficacy of ALS inhibitors on a putatively tolerant population sprayed annually with ALS inhibitors and an adjacent...

  19. Nicotinamide phosphoribosyltransferase inhibitors, design, preparation and SAR

    DEFF Research Database (Denmark)

    Christensen, Mette Knak; Erichsen, Kamille Dumong; Olesen, Uffe Hogh

    2013-01-01

    Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. Using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described and compounds optimize...

  20. FY 1994 Annual Work Plan

    Energy Technology Data Exchange (ETDEWEB)

    1993-09-30

    In accordance with the Inspector General`s Strategic Planning Policy directive, the Office of Inspector General (OIG) annually updates its Strategic Plan with budgetary and program guidance for the next fiscal year. The program guidance identifies and establishes priorities for OIG coverage of important DOE issues and operations, provides the basis for assigning OIG resources, and is the source for issues covered in Assistant Inspectors General annual work plans. The Office of the Assistant Inspector General for Audits (AIGA) publishes an Annual Work Plan in September of each year. The plan includes the OIG program guidance and shows the commitment of resources necessary to accomplish the assigned work and meet our goals. The program guidance provides the framework within which the AIGA work will be planned and accomplished. Audits included in this plan are designed to help insure that the requirements of our stakeholders have been considered and blended into a well balanced audit program.

  1. Allosteric small-molecule kinase inhibitors

    DEFF Research Database (Denmark)

    Wu, Peng; Clausen, Mads Hartvig; Nielsen, Thomas E.

    2015-01-01

    current barriers of kinase inhibitors, including poor selectivity and emergence of drug resistance. In spite of the small number of identified allosteric inhibitors in comparison with that of inhibitors targeting the ATP pocket, encouraging results, such as the FDA-approval of the first small...

  2. 78th Annual Meeting | Annual Meetings | Events | Indian Academy of ...

    Indian Academy of Sciences (India)

    78th Annual Meeting. Dates : 2 to 4 November 2012. Venue : Wadia Institute of Himalayan Geology, Dehra Dun. Videos of Talks. The emerging facets of Raman effect: A. K. Sood, Indian Institute of Science, Bengaluru; Cinema for health: Mohan Agashe, Pune; The challenge of climate change: Shyam Saran, Chairman, ...

  3. 77th Annual Meeting | Annual Meetings | Events | Indian Academy of ...

    Indian Academy of Sciences (India)

    77th Annual Meeting. Dates : 18 to 20 November 2011. Venue : Physical Research Laboratory, Ahmedabad. Videos of Talks. Fascinating flow of complex fluids . jamming, order and chaos: A. K. Sood, Chairman, Indian Institute of Science, Bengaluru; A creative melancholy: the paintings of Rabindranath Tagore: Sudhir ...

  4. Proteasome inhibitors with photocontrolled activity.

    Science.gov (United States)

    Hansen, Mickel J; Velema, Willem A; de Bruin, Gerjan; Overkleeft, Herman S; Szymanski, Wiktor; Feringa, Ben L

    2014-09-22

    Proteasome inhibitors are widely used in cancer treatment as chemotherapeutic agents. However, their employment often results in severe side effects, due to their non-specific cytotoxicity towards healthy tissue. This problem might be overcome by using a photopharmacological approach, that is, by attaining external, dynamic, spatiotemporal photocontrol over the activity of a cytotoxic agent, achieved by the introduction of a photoswitchable moiety into its molecular structure. Here we describe the design, synthesis, and activity of photoswitchable proteasome inhibitors. Substantial differences in proteasome inhibitory activity in cell extracts were observed before and after irradiation with light. The presented results show potential for the development of chemotherapeutic agents that can be switched on and off with light, constituting a new strategy for spatiotemporally modulating proteasomal activity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Small-molecule arginase inhibitors.

    Science.gov (United States)

    Ivanenkov, Yan A; Chufarova, Nina V

    2014-01-01

    Arginase is an enzyme that metabolizes L-arginine to L-ornithine and urea. In addition to its fundamental role in the hepatic ornithine cycle, it also influences the immune systems in humans and mice. Arginase participates in many inflammatory disorders by decreasing the synthesis of nitric oxide and inducing fibrosis and tissue regeneration. L-arginine deficiency, which is modulated by myeloid cell arginase, suppresses T-cell immune response. This mechanism plays a fundamental role in inflammation-associated immunosuppression. Pathogens can synthesize their own arginase to elude immune reaction. Small-molecule arginase inhibitors are currently described as promising therapeutics for the treatment of several diseases, including allergic asthma, inflammatory bowel disease, ulcerative colitis, cardiovascular diseases (atherosclerosis and hypertension), diseases associated with pathogens (e.g., Helicobacter pylori, Trypanosoma cruzi, Leishmania, Mycobacterium tuberculosis and Salmonella), cancer and induced or spontaneous immune disorders. This article summarizes recent patents in the area of arginase inhibitors and discusses their properties.

  6. Proteasome inhibitors in cancer therapy

    Directory of Open Access Journals (Sweden)

    Wioletta Romaniuk

    2015-12-01

    Full Text Available Proteasomes are multisubunit enzyme complexes. They contain three enzymatic active sites which are termed chymotrypsin-like, trypsin-like, and caspase-like. The elementary function of the proteasomes is degradation of damaged proteins. Proteasome inhibition leads to accumulation of damaged protein, which leads to caspase activation and cell death. This relationship is used in cancer therapy. Bortezomib is the first proteasome inhibitor approved by the US Food and Drug Administration for the treatment of relapsed/refractory multiple myeloma. Carfilzomib belongs to the second generation of drugs, which was approved by the US FDA in 2012. Currently in the study phase there are four new inhibitors: ixazomib (MLN9780/MLN2238, delanzomib (CEP-18770, oprozomib (ONX0912/PR-047 and marizomib (NPI-0052.

  7. Natural Inhibitors of Maillard Browning

    Science.gov (United States)

    2013-12-01

    incorporated into pre-selected candidate ration components for evaluation via storage, sensory and chemical analysis. The concentration of inhibitor was...inhibiting Maillard browning, also known as non-enzymatic browning, a complex reaction which can lead to darkening of color, off- odors , off-flavors...nutritional intake, and decrease waste due to non-consumption of sensory degraded ration components. 1.1 Maillard Browning Maillard browning, also

  8. Proton Pump Inhibitors and Gastritis

    OpenAIRE

    Suzuki, Masayuki; Suzuki, Hidekazu; Hibi, Toshifumi

    2008-01-01

    Proton pump inhibitors (PPIs) are novel compounds that strongly inhibit the H+/K+-ATPase in the gastric parietal cells to cause profound suppression of acid secretion. Acid-generating ATPase, also known as vacuolar-type ATPase, is located in the lysozomes of leukocytes and osteoclasts and its activity is also reportedly influenced by treatment with PPIs. This concept is supported by the results of studies using autoradiography in which 3H-Lansoprazole uptake sites were clearly detected in the...

  9. Economic Evaluation of PCSK9 Inhibitors in Reducing Cardiovascular Risk from Health System and Private Payer Perspectives.

    Directory of Open Access Journals (Sweden)

    Alejandro Arrieta

    Full Text Available The introduction of Proprotein covertase subtilisin/kexin type 9 (PCSK9 inhibitors has been heralded as a major advancement in reducing low-density lipoprotein cholesterol levels by nearly 50%. However, concerns have been raised on the added value to the health care system in terms of their costs and benefits. We assess the cost-effectiveness of PCSK9 inhibitors based on a decision-analytic model with existing clinical evidence. The model compares a lipid-lowering therapy based on statin plus PCSK9 inhibitor treatment with statin treatment only (standard therapy. From health system perspective, incremental cost per quality adjusted life years (QALYs gained are presented. From a private payer perspective, return-on-investment and net present values over patient lifespan are presented. At the current annual cost of $14,000 to $15,000, PCSK9 inhibitors are not cost-effective at an incremental cost of about $350,000 per QALY. Moreover, for every dollar invested in PCSK9 inhibitors, the private payer loses $1.98. Our study suggests that the annual treatment price should be set at $4,250 at a societal willingness-to-pay of $100,000 per QALY. However, we estimate the breakeven price for private payer is only $600 per annual treatment. At current prices, our study suggests that PCSK9 inhibitors do not add value to the U.S. health system and their provision is not profitable for private payers. To be the breakthrough drug in the fight against cardiovascular disease, the current price of PCSK9 inhibitors must be reduced by more than 70%.

  10. Stabilization versus inhibition of TAFIa by competitive inhibitors in vitro

    NARCIS (Netherlands)

    Walker, J.B.; Hughes, B.; James, I.; Haddock, P.; Kluft, C.; Bajzar, L.

    2003-01-01

    Two competitive inhibitors of TAFIa (activated thrombin-activable fibrinolysis inhibitor), 2-guanidinoethyl-mercaptosuccinic acid and potato tuber carboxypeptidase inhibitor, variably affect fibrinolysis of clotted human plasma. Depending on their concentration, the inhibitors shortened, prolonged,

  11. Tender for printing annual report

    Indian Academy of Sciences (India)

    Paper : 130 GSM imported art paper for text. 300 GSM imported art card for cover. Colour Four colour both text & cover. Binding Perfect. Lamination : matt Finish lamination on cover. Input Soft Copy. Quantity : 300 English & 50 Hindi. Packaging : All book Annual Report are first to be shrinked packed in set of 10 books.

  12. FY 1994 Annual Work Plan

    Energy Technology Data Exchange (ETDEWEB)

    1993-10-01

    This is the third Office of Inspector General (OIG)Annual Work Plan. Its purpose is to summarize work completed in Fiscal Year (FY) 1993, identify ongoing projects from previous fiscal years which the OIG intends to continue into FY 1994, and announce planned projects which the OIG intends to begin in FY 19994.

  13. Annual report 1991-92

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1992-12-31

    The Agency`s sole objective has been to reduce regional electrical rate disparities by equalizing generation and transmission (upstream) costs province-wide. Operated under the jurisdiction of the Dept. of Energy, this annual report of the Agency covers Agency operations, mandate, pooling process, and shielding of low-cost utilities. A financial statement is included.

  14. 1982 laser program annual report

    Energy Technology Data Exchange (ETDEWEB)

    Hendricks, C.D.; Grow, G.R. (eds.)

    1983-08-01

    This annual report covers the following eight sections: (1) laser program review, (2) laser systems and operation, (3) target design, (4) target fabrication, (5) fusion experiments program, (6) Zeus laser project, (7) laser research and development, and (8) energy applications. (MOW)

  15. Annual report 1996; Aarsrapport 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-12-01

    The annual report from the Norwegian Institute for Air Research presents the activities at the institute. The activities cover fields like motor traffic and air quality of urban areas, acid precipitation, the ozone layer, advanced environmental monitoring systems, environmental contamination, and environmental problems in Arctic. 17 figs., 1 tab.

  16. Spinoff 1978: An Annual Report.

    Science.gov (United States)

    National Aeronautics and Space Administration, Washington, DC.

    This abstract is the annual report of NASA's Technology Utilization Program, which is charged with promoting and stimulating the practical application of government-sponsored aerospace technology. The report is organized in three sections: (1) aerospace aims; (2) technology twice used; and (3) technology utilization. Section 1 outlines NASA's…

  17. CIEE 1993 annual conference: Program

    Energy Technology Data Exchange (ETDEWEB)

    1993-08-01

    The California Institute for Energy efficiency`s third annual conference highlights the results of CIEE-sponsored multiyear research in three programs: Building Energy Efficiency, Air Quality Impacts of Energy Efficiency, and End-Use Resource Planning. Results from scoping studies, Director`s discretionary research, and exploratory research are also featured.

  18. Emerging therapies for atopic dermatitis: JAK inhibitors.

    Science.gov (United States)

    Cotter, David G; Schairer, David; Eichenfield, Lawrence

    2018-03-01

    The Janus kinase-signal transducer and activator of transcription pathway is a conserved master regulator of immunity and myeloproliferation. Advanced understanding of this pathway has led to development of targeted inhibitors of Janus kinases (Jakinibs). As a class, JAK inhibitors effectively treat a multitude of hematologic and inflammatory diseases. Given such success, use of JAK inhibitors for mitigation of atopic dermatitis is under active investigation. Herein, we review the evolving data on the safety and efficacy of JAK inhibitors in treatment of atopic dermatitis. Although it is still early in the study of JAK inhibitors for atopic dermatitis, evidence identifies JAK inhibitors as effective alternatives to conventional therapies. Nonetheless, multiple large safety and efficacy trials are needed before widespread use of JAK inhibitors can be advocated for atopic dermatitis. Copyright © 2017. Published by Elsevier Inc.

  19. [Effects of biochar and nitrification inhibitor incorporation on global warming potential of a vegetable field in Nanjing, China].

    Science.gov (United States)

    Li, Bo; Li, Qiao-Ling; Fan, Chang-Hua; Sun, Li-Ying; Xiong, Zheng-Qin

    2014-09-01

    The influences of biochar and nitrification inhibitor incorporation on global warming potential (GWP) of a vegetable field were studied using the static chamber and gas chromatography method. Compared with the treatments without biochar addition, the annual GWP of N2O and CH4 and vegetable yield were increased by 8.7%-12.4% and 16.1%-52.5%, respectively, whereas the greenhouse gas intensity (GHGI) were decreased by 5.4%-28.7% following biochar amendment. Nitrification inhibitor significantly reduced the N2O emission while had little influence on CH4 emission, decreased GWP by 17.5%-20.6%, increased vegetable yield by 21.2%-40.1%, and decreased the GHGI significantly. The combined application of biochar and nitrification inhibitor significantly increased both vegetable yield and GWP, but to a greater extent for vegetable yield. Therefore, nitrification inhibitor incorporation could be served as an appropriate practice for increasing vegetable yield and mitigating GHG emissions in vegetable field.

  20. Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its Analogs: Evaluation of Their Free Radical Scavenging and Monoamine Oxidase and Cholinesterase Inhibitory Activities.

    Science.gov (United States)

    Takao, Koichi; Toda, Kazuhiro; Saito, Takayuki; Sugita, Yoshiaki

    2017-01-01

    A series of cinnamic acid derivatives, amides (1-12) and esters (13-22), were synthesized, and structure-activity relationships for antioxidant activity, and monoamine oxidases (MAO) A and B, acetylcholinesterase, and butyrylcholinesterase (BChE) inhibitory activities were analyzed. Among the synthesized compounds, compounds 1-10, 12-18, and rosmarinic acid (23), which contained catechol, o-methoxyphenol or 5-hydroxyindole moieties, showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. Compounds 9-11, 15, 17-22 showed potent and selective MAO-B inhibitory activity. Compound 20 was the most potent inhibitor of MAO-B. Compounds 18 and 21 showed moderate BChE inhibitory activity. In addition, compound 18 showed potent antioxidant activity and MAO-B inhibitory activity. In a comparison of the cinnamic acid amides and esters, the amides exhibited more potent DPPH free radical scavenging activity, while the esters showed stronger inhibitory activities against MAO-B and BChE. These results suggested that cinnamic acid derivatives such as compound 18, p-coumaric acid 3,4-dihydroxyphenethyl ester, and compound 20, p-coumaric acid phenethyl ester, may serve as lead compounds for the development of novel MAO-B inhibitors and candidate lead compounds for the prevention or treatment of Alzheimer's disease.

  1. Inhibitor of Phosphodiestearse-4 improves memory deficits, oxidative stress, neuroinflammation and neuropathological alterations in mouse models of dementia of Alzheimer's Type.

    Science.gov (United States)

    Kumar, Amit; Singh, Nirmal

    2017-04-01

    The study investigates the potential of Rolipram a phosphodiesterase-4 inhibitor in cognitive deficits induced by streptozotocin (STZ, 3mg/kg intracerebroventricularly) and natural ageing in mice. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. Extent of oxidative stress was measured by estimating the levels of brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity was also estimated. The brain activity of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and ageing results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice and aged mice exhibited a marked accentuation of AChE activity, TBARS and MPO activity along with fall in GSH level. Further the stained micrographs of STZ treated mice and aged mice indicate pathological changes, severe neutrophilic infiltration and amyloid deposition. Rolipram treatment significantly attenuated STZ induced and age related memory deficits, biochemical and histopathological alterations. The findings demonstrate the potential of Rolipram in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-amyloid, anti-oxidative and anti-inflammatory effects. The study concludes that PDE-4 can be explored as a potential therapeutic target in dementia. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. Global gene expression in larval zebrafish (Danio rerio) exposed to selective serotonin reuptake inhibitors (fluoxetine and sertraline) reveals unique expression profiles and potential biomarkers of exposure.

    Science.gov (United States)

    Park, June-Woo; Heah, Tze Ping; Gouffon, Julia S; Henry, Theodore B; Sayler, Gary S

    2012-08-01

    Larval zebrafish (Danio rerio) were exposed (96 h) to selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline and changes in transcriptomes analyzed by Affymetrix GeneChip Zebrafish Array were evaluated to enhance understanding of biochemical pathways and differences between these SSRIs. The number of genes differentially expressed after fluoxetine exposure was 288 at 25 μg/L and 131 at 250 μg/L; and after sertraline exposure was 33 at 25 μg/L and 52 at 250 μg/L. Same five genes were differentially regulated in both SSRIs indicating shared molecular pathways. Among these, the gene coding for FK506 binding protein 5, annotated to stress response regulation, was highly down-regulated in all treatments (results confirmed by qRT-PCR). Gene ontology analysis indicated at the gene expression level that regulation of stress response and cholinesterase activities were influenced by these SSRIs, and suggested that changes in transcription of these genes could be used as biomarkers of SSRI exposure. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. Synthesis of Selective Butyrylcholinesterase Inhibitors Coupled between α-Lipoic Acid and Polyphenols by Using 2-(Piperazin-1-yl)ethanol Linker

    Energy Technology Data Exchange (ETDEWEB)

    Yeun, Go Heun; Lee, Seung Hwan; LIm, Yong Bae; Lee, Hye Sook; Lee, Bong Ho; Park, Jeong Ho [Hanbat National Univ., Daejeon (Korea, Republic of); Won, Mooho [Kangwon National Univ., Chuncheon (Korea, Republic of)

    2013-04-15

    In the previous paper (Bull. Korean Chem. Soc., 2011, 32, 2997), the hybrid molecules between α-lipoic acid (ALA) and polyphenols (PPs) connected with neutral 2-(2-aminoethoxy)ethanol linker (linker-1) showed new biological activity such as butyrylcholinesterase (BuChE) inhibition. In order to increase the binding affinity of the hybrid compounds to cholinesterase (ChE), the neutral 2-(2-aminoethoxy)ethanol (linker 1) was switched to the cationic 2-(piperazin-1-yl)ethanol linker (linker 2). The IC{sub 50} values of the linker-2 hybrid molecules for BuChE inhibition were lower than those of linker-1 hybrid molecules (except 9-2) and they also had the same great selectivity for BuChE over AChE (> 800 fold) as linker-1 hybrid molecules. ALA-acetyl caffeic acid (10-2, ALA-AcCA) was shown as an effective inhibitor of BuChE (IC{sub 50} = 0.44 ± 0.24 μM). A kinetic study using 7-2 showed that it is the same mixed type inhibition as 7-1. Its inhibition constant (Ki) to BuChE is 4.3 ± 0.09 μM.

  4. 2016 Annual Technology Baseline (ATB) - Webinar Presentation

    Energy Technology Data Exchange (ETDEWEB)

    Cole, Wesley; Kurup, Parthiv; Hand, Maureen; Feldman, David; Sigrin, Benjamin; Lantz, Eric; Stehly, Tyler; Augustine, Chad; Turchi, Craig; Porro, Gian; O' Connor, Patrick; Waldoch, Connor

    2016-09-13

    This deck was presented for the 2016 Annual Technology Baseline Webinar. The presentation describes the Annual Technology Baseline, which is a compilation of current and future cost and performance data for electricity generation technologies.

  5. U.S. Annual Climatological Summaries

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Annual Climatological Summary contains historical monthly and annual summaries for over 8000 U.S. locations. Observing stations are located in the United States of...

  6. Secretary's annual report to Congress

    Energy Technology Data Exchange (ETDEWEB)

    None

    1980-01-01

    This second annual report of the DOE covers activities of all elements of the department except the independent FERC, which issues its own annual report. Individual chapters concern a posture statement, conservation, solar and other renewable energy, fossil energy, electric energy, nuclear energy, the environment, defense programs, international programs, general science programs, energy information, economic regulation, energy production, and support operations. The following appendixes are also included: foreign direct investments in US energy sources and supplies, exports of energy resources by foreign companies, major recipients of DOE funding, actions taken regarding disclosure of energy assets by DOE employees, financial assistance programs for alternative fuel demonstration facilities, and 1978 budget summary. 16 figures, 56 tables. (RWR)

  7. Annual report to Congress, 1998

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1999-04-01

    Section 205 of the Department of Energy Organization Act of 1977 established the Energy Information Administration (EIA). One of the mandates in this legislation is that EIA prepare for Congress an annual report summarizing both activities and information collected and published. EIA`s major 1998 accomplishments are profiled in the body of this edition of the Annual Report to Congress. Appendix A contains abstracts of significant reports issued by EIA in 1998 and a chart of all titles and a list of all feature articles published during the year. Appendix B contains graphs of selected performance measures. Appendix C lists contact information for EIA subject matter specialists. Appendix D lists the major laws which form the basis of EIA`s legislative mandate.

  8. Annual report to Congress 1997

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-07-01

    Section 205 of the Department of Energy Organization Act of 1977 established the Energy Information Administration (EIA). One of the mandates in this legislation is that EIA prepare for Congress an annual report summarizing both activities and information collected and published. EIA`s major 1997 accomplishments are profiled in the body of this edition of the Annual Report to Congress. Appendix A contains abstracts of significant reports issued by EIA in 1997, and a chart of all titles and a list of all feature articles published during the year. Appendix B contains graphs of selected performance measures. Appendix C lists contact information for EIA subject matter specialists. Appendix D lists the major laws which form the basis of EIA`s legislative mandate.

  9. Determining Mean Annual Energy Production

    DEFF Research Database (Denmark)

    Kofoed, Jens Peter; Folley, Matt

    2016-01-01

    This robust book presents all the information required for numerical modelling of a wave energy converter, together with a comparative review of the different available techniques. The calculation of the mean annual energy production (MAEP) is critical to the assessment of the levelized cost...... of energy for a wave energy converter or wave farm. Fundamentally, the MAEP is equal to the sum of the product of the power capture of a set of sea-states and their average annual occurrence. In general, it is necessary in the calculation of the MAEP to achieve a balance between computational demand...... obtained through system identification. The traditional method for representing the wave climate is using a scatter table, indexed by significant wave height and energy period; however, it has been found that this can lead to high errors in the MAEP due to the necessary assumptions regarding spectral shape...

  10. CAES Annual Report FY 2011

    Energy Technology Data Exchange (ETDEWEB)

    Kortny Rolston

    2011-10-01

    The Center for Advanced Energy Studies was created to lead research programs important to the nation, attract students and faculty to the Idaho universities and act as a catalyst for technology-based economic development. CAES is striving to meet those goals by continuing to develop its infrastructure and equipment capabilities, expand its research portfolio and bolster Idaho's energy workforce. This Annual Report details the progress CAES made in FY 2011 toward fulfilling its research, education and economic development missions.

  11. American Psychological Association annual report.

    Science.gov (United States)

    2010-01-01

    Presents the 2009 American Psychological Association annual report. It highlights a very important year for APA and psychology by summarizing activities within each directorate. It describes strides made toward the goal of infusing psychology into the health care marketplace and of bringing psychology-and the unique skills of psychologists-to the attention of the public. This report aims to give insight into the contributions psychologists make to our communities and our country. 2010 APA, all rights reserved.

  12. 55th Annual Fuze Conference

    Science.gov (United States)

    2011-05-26

    supporting piezoresistive elements  Full Wheatstone - bridge  Functional principle:  Inertial forces cause deflection of plate  Straining of...Approval Process Gabe Soto, Chairman, Fuze and Initiation System Technical Review Panel Air Force Safety Approval Process Matt Bridge OPEN SESSIONS...Matt Bridge  11:50 Harry Diamond Fuzing Excellence Award Ceremony  12:00 Lunch May 25, 2011 - General Session (AM) 55th Annual Fuze

  13. 77 FR 61238 - Annual Stress Test

    Science.gov (United States)

    2012-10-09

    ... Office of the Comptroller of the Currency 12 CFR Part 46 RIN 1557-AD58 Annual Stress Test AGENCY: Office...'') which requires certain companies to conduct annual stress tests pursuant to regulations prescribed by... ``covered institutions'') to conduct an annual stress test as prescribed by this rule. Under the final rule...

  14. 77 FR 16484 - Annual Stress Test

    Science.gov (United States)

    2012-03-21

    ... Office of the Comptroller of the Currency 12 CFR Part 46 RIN 1557-AD58 Annual Stress Test AGENCY: Office... with total consolidated assets of more than $10 billion to conduct an annual stress test and comply... consolidated assets in excess of $10 billion to conduct annual stress tests pursuant to regulations prescribed...

  15. Risø annual report 2001

    DEFF Research Database (Denmark)

    2002-01-01

    In this annual report, we present a small selection of Risø’s achievements in 2001. A more detailed review of Risø’s projects can be found in the Risø Annual Accounts for 2001 as well as in the annual progress reports prepared by the individual researchdepartments....

  16. 76 FR 69239 - Annual Retail Trade Survey

    Science.gov (United States)

    2011-11-08

    ... survey, the Census Bureau will collect data covering annual sales, annual e-commerce sales, year-end... receivables, and, for selected industries, merchandise line sales, and percent of e-commerce sales to..., annual e-commerce sales, purchases, total operating expenses, accounts receivables, and year-end...

  17. 2016 Annual Technology Baseline (ATB)

    Energy Technology Data Exchange (ETDEWEB)

    Cole, Wesley; Kurup, Parthiv; Hand, Maureen; Feldman, David; Sigrin, Benjamin; Lantz, Eric; Stehly, Tyler; Augustine, Chad; Turchi, Craig; O' Connor, Patrick; Waldoch, Connor

    2016-09-01

    Consistent cost and performance data for various electricity generation technologies can be difficult to find and may change frequently for certain technologies. With the Annual Technology Baseline (ATB), National Renewable Energy Laboratory provides an organized and centralized dataset that was reviewed by internal and external experts. It uses the best information from the Department of Energy laboratory's renewable energy analysts and Energy Information Administration information for conventional technologies. The ATB will be updated annually in order to provide an up-to-date repository of current and future cost and performance data. Going forward, we plan to revise and refine the values using best available information. The ATB includes both a presentation with notes (PDF) and an associated Excel Workbook. The ATB includes the following electricity generation technologies: land-based wind; offshore wind; utility-scale solar PV; concentrating solar power; geothermal power; hydropower plants (upgrades to existing facilities, powering non-powered dams, and new stream-reach development); conventional coal; coal with carbon capture and sequestration; integrated gasification combined cycle coal; natural gas combustion turbines; natural gas combined cycle; conventional biopower. Nuclear laboratory's renewable energy analysts and Energy Information Administration information for conventional technologies. The ATB will be updated annually in order to provide an up-to-date repository of current and future cost and performance data. Going forward, we plan to revise and refine the values using best available information.

  18. Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease.

    Science.gov (United States)

    Kazi, Dhruv S; Moran, Andrew E; Coxson, Pamela G; Penko, Joanne; Ollendorf, Daniel A; Pearson, Steven D; Tice, Jeffrey A; Guzman, David; Bibbins-Domingo, Kirsten

    2016-08-16

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were recently approved for lowering low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD) and have potential for broad ASCVD prevention. Their long-term cost-effectiveness and effect on total health care spending are uncertain. To estimate the cost-effectiveness of PCSK9 inhibitors and their potential effect on US health care spending. The Cardiovascular Disease Policy Model, a simulation model of US adults aged 35 to 94 years, was used to evaluate cost-effectiveness of PCSK9 inhibitors or ezetimibe in heterozygous FH or ASCVD. The model incorporated 2015 annual PCSK9 inhibitor costs of $14,350 (based on mean wholesale acquisition costs of evolocumab and alirocumab); adopted a health-system perspective, lifetime horizon; and included probabilistic sensitivity analyses to explore uncertainty. Statin therapy compared with addition of ezetimibe or PCSK9 inhibitors. Lifetime major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, or stroke), incremental cost per quality-adjusted life-year (QALY), and total effect on US health care spending over 5 years. Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent 316,300 MACE at a cost of $503,000 per QALY gained compared with adding ezetimibe to statins (80% uncertainty interval [UI], $493,000-$1,737,000). In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE compared with adding ezetimibe at $414,000 per QALY (80% UI, $277,000-$1,539,000). Reducing annual drug costs to $4536 per patient or less would be needed for PCSK9 inhibitors to be cost-effective at less than $100,000 per QALY. At 2015 prices, PCSK9 inhibitor use in all eligible patients was estimated to reduce cardiovascular care costs by $29 billion over 5 years, but drug costs increased by an estimated $592 billion (a 38

  19. Targeting telomerase with radiolabeled inhibitors.

    Science.gov (United States)

    Waghorn, Philip A; Jackson, Mark R; Gouverneur, Veronique; Vallis, Katherine A

    2017-01-05

    The expression of telomerase in approximately 85% of cancers and its absence in the majority of normal cells makes it an attractive target for cancer therapy. However the lag period between initiation of telomerase inhibition and growth arrest makes direct inhibition alone an insufficient method of treatment. However, telomerase inhibition has been shown to enhance cancer cell radiosensitivity. To investigate the strategy of simultaneously inhibiting telomerase while delivering targeted radionuclide therapy to cancer cells, 123 I-radiolabeled inhibitors of telomerase were synthesized and their effects on cancer cell survival studied. An 123 I-labeled analogue of the telomerase inhibitor MST-312 inhibited telomerase with an IC 50 of 1.58 μM (MST-312 IC 50 : 0.23 μM). Clonogenic assays showed a dose dependant effect of 123 I-MST-312 on cell survival in a telomerase positive cell line, MDA-MB-435. Copyright © 2016 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

  20. Vanadium Compounds as PTP Inhibitors

    Directory of Open Access Journals (Sweden)

    Elsa Irving

    2017-12-01

    Full Text Available Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs and protein tyrosine phosphatases (PTPs. Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought to inhibit PTPs, thus acting as a pan-inhibitor of this enzyme superfamily. We discuss recent developments in the biological and biochemical actions of more complex vanadium derivatives, including decavanadate and in particular the growing number of oxidovanadium compounds with organic ligands. Pre-clinical studies involving these compounds are discussed in the anti-diabetic and anti-cancer contexts. Although in many cases PTP inhibition has been implicated, it is also clear that many such compounds have further biochemical effects in cells. There also remain concerns surrounding off-target toxicities and long-term use of vanadium compounds in vivo in humans, hindering their progress through clinical trials. Despite these current misgivings, interest in these chemicals continues and many believe they could still have therapeutic potential. If so, we argue that this field would benefit from greater focus on improving the delivery and tissue targeting of vanadium compounds in order to minimize off-target toxicities. This may then harness their full therapeutic potential.

  1. Proteasome inhibitor patents (2010 - present).

    Science.gov (United States)

    Metcalf, Rainer; Scott, Latanya M; Daniel, Kenyon G; Dou, Q Ping

    2014-04-01

    Over the past 3 years, numerous patents and patent applications have been submitted and published involving compounds designed to inhibit the proteasome. Proteasome inhibition has been of great interest in cancer research since disruption of proteolysis leads to a significant buildup of cytotoxic proteins and activation of apoptotic pathways, particularly in rapidly proliferating cells. The current standards in proteasome inhibition are the only FDA-approved inhibitors, bortezomib and carfilzomib. Although these drugs are quite effective in treating multiple myeloma and other blood tumors, there are shortcomings, including toxicities and resistance. Most of the current patents attempt to improve on existing compounds, by increasing bioavailability and selectivity, while attempting to reduce toxicity. A general categorization of similar compounds was employed to evaluate and compare drug design strategies. This review focuses on novel compounds and subsequent analogs developed for proteasome inhibition, used in preventing and treating human cancers. A comprehensive description and categorization of patents related to each type of compound and its derivatives, as well as their uses and efficacies as anticancer agents is included. A review of combination therapy patents has also been included. Although there are many diverse chemical scaffolds being published, there are few patented proteasome inhibitors whose method of inhibition is genuinely novel. Most patents utilize a destructive chemical warhead to attack the catalytic threonine residue of the proteasome active sites. Few patents try to depart from this, emphasizing the need for developing new mechanisms of action and specific targeting.

  2. Proton pump inhibitors and osteoporosis

    DEFF Research Database (Denmark)

    Andersen, Bjarne Nesgaard; Johansen, Per Birger; Abrahamsen, Bo

    2016-01-01

    PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months and a di......PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months...... and a discussion of these findings and how this has influenced our understanding of this association, the clinical impact and the underlying pathophysiology. RECENT FINDINGS: New studies have further strengthened existing evidence linking use of PPIs to osteoporosis. Short-term use does not appear to pose a lower...... risk than long-term use. There is a continued lack of conclusive studies identifying the pathogenesis. Direct effects on calcium absorption or on osteoblast or osteoclast action cannot at present plausibly explain the mechanism. SUMMARY: The use of PPIs is a risk factor for development of osteoporosis...

  3. Laura: Soybean variety lacking Kunitz trypsin inhibitor

    Directory of Open Access Journals (Sweden)

    Srebrić Mirjana

    2010-01-01

    Full Text Available Grain of conventional soybean varieties requires heat processing to break down trypsin inhibitor's activity before using as food or animal feed. At the same time, protein denaturation and other qualitative changes occur in soybean grain, especially if the temperature of heating is not controlled. Two types of trypsin inhibitor were found in soybean grain the Kunitz trypsin inhibitor and the Bowman-Birk inhibitor. Mature grain of soybean Laura is lacking Kunitz trypsin inhibitor. Grain yield of variety Laura is equal to high yielding varieties from the maturity group I, where it belongs. Lacking of Kunitz-trypsin inhibitor makes soybean grain suitable for direct feeding in adult non ruminant animals without previous thermal processing. Grain of variety Laura can be processed for a shorter period of time than conventional soybeans. This way we save energy, and preserve valuable nutritional composition of soybean grain, which is of interest in industrial processing.

  4. An inhibitor of phospholipase D in saliva

    Science.gov (United States)

    Dawson, Rex M. C.; Hemington, Norma

    1974-01-01

    1. Bovine, dog and human saliva contain substances which inhibit the soluble phospholipase D present in grass leaf or celery stalk. 2. The inhibitor in bovine saliva is of high molecular weight and exhibits considerable stability to heat, acids and alkalis. 3. The inhibitor has been purified free from salivary mucoprotein. 4. It is suggested that the inhibitor could protect the upper alimentary tract of a herbage-eating animal from the necrotic action of phospholipase D. PMID:4376946

  5. QSAR for cholinesterase inhibition by organophosphorus esters and CNDO/2 calculations for organophosphorus ester hydrolysis. [quantitative structure-activity relationship, complete neglect of differential overlap

    Science.gov (United States)

    Johnson, H.; Kenley, R. A.; Rynard, C.; Golub, M. A.

    1985-01-01

    Quantitative structure-activity relationships were derived for acetyl- and butyrylcholinesterase inhibition by various organophosphorus esters. Bimolecular inhibition rate constants correlate well with hydrophobic substituent constants, and with the presence or absence of cationic groups on the inhibitor, but not with steric substituent constants. CNDO/2 calculations were performed on a separate set of organophosphorus esters, RR-primeP(O)X, where R and R-prime are alkyl and/or alkoxy groups and X is fluorine, chlorine or a phenoxy group. For each subset with the same X, the CNDO-derived net atomic charge at the central phosphorus atom in the ester correlates well with the alkaline hydrolysis rate constant. For the whole set of esters with different X, two equations were derived that relate either charge and leaving group steric bulk, or orbital energy and bond order to the hydrolysis rate constant.

  6. Histone deacetylase inhibitors in cancer therapy.

    Science.gov (United States)

    Lane, Andrew A; Chabner, Bruce A

    2009-11-10

    Epigenetic processes are implicated in cancer causation and progression. The acetylation status of histones regulates access of transcription factors to DNA and influences levels of gene expression. Histone deacetylase (HDAC) activity diminishes acetylation of histones, causing compaction of the DNA/histone complex. This compaction blocks gene transcription and inhibits differentiation, providing a rationale for developing HDAC inhibitors. In this review, we explore the biology of the HDAC enzymes, summarize the pharmacologic properties of HDAC inhibitors, and examine results of selected clinical trials. We consider the potential of these inhibitors in combination therapy with targeted drugs and with cytotoxic chemotherapy. HDAC inhibitors promote growth arrest, differentiation, and apoptosis of tumor cells, with minimal effects on normal tissue. In addition to decompaction of the histone/DNA complex, HDAC inhibition also affects acetylation status and function of nonhistone proteins. HDAC inhibitors have demonstrated antitumor activity in clinical trials, and one drug of this class, vorinostat, is US Food and Drug Administration approved for the treatment of cutaneous T-cell lymphoma. Other inhibitors in advanced stages of clinical development, including depsipeptide and MGCD0103, differ from vorinostat in structure and isoenzyme specificity, and have shown activity against lymphoma, leukemia, and solid tumors. Promising preclinical activity in combination with cytotoxics, inhibitors of heat shock protein 90, and inhibitors of proteasome function have led to combination therapy trials. HDAC inhibitors are an important emerging therapy with single-agent activity against multiple cancers, and have significant potential in combination use.

  7. Structure Related Inhibition of Enzyme Systems in Cholinesterases and BACE1 In Vitro by Naturally Occurring Naphthopyrone and Its Glycosides Isolated from Cassia obtusifolia

    Directory of Open Access Journals (Sweden)

    Srijan Shrestha

    2017-12-01

    Full Text Available Cassia obtusifolia Linn. have been used to improve vision, inflammatory diseases, and as hepatoprotective agents and to promote urination from ancient times. In the present study, we investigated the influence of glycosylation of components of C. obtusifolia and structure-activity relationships (SARs with respect to the inhibition of acetylcholinesterase (AChE, butyrylcholinesterase (BChE, and β-site amyloid precursor protein (APP-cleaving enzyme 1 (BACE1, which are related to Alzheimer’s disease (AD. All six C. obtusifolia-derived compounds, rubrofusarin (1, rubrofusarin 6-O-β-d-glucopyranoside (2, rubrofusarin 6-O-β-d-gentiobioside (3, nor-rubrofusarin 6-O-β-d-glucoside (4, isorubrofusarin 10-O-β-d-gentiobioside (5, and rubrofusarin 6-O-β-d-triglucoside (6 showed promising inhibitory activity against AChE/BACE1. Compounds 3 and 4 showed most significant inhibition against AChE and BACE1, respectively. The SARs results emphasized the importance of gentiobiosyl moiety in the rubrofusarin for AChE inhibition, whereas the presence of hydroxyl group at C-8 and the glucosyl moiety at the C-6 position in the nor-rubrofusarin appeared to largely determine BACE1 inhibition. Kinetics and docking studies showed the lowest binding energy and highest affinity for mixed-type inhibitors, 3 and 4. Hydrophobic bonds interactions and the number of hydrogen bonds determined the strength of the protein-inhibitor interaction. These results suggest that C. obtusifolia and its constituents have therapeutic potential, and that the SARs of its active components are further explored with a view towards developing a treatment for AD.

  8. [Development of new antiatherosclerotic agents--ACAT inhibitors and CETP inhibitors].

    Science.gov (United States)

    Miyazaki, A; Horiuchi, S

    1999-12-01

    Development of new antiatherosclerotic agents were reviewed focusing on ACAT inhibitors and CETP inhibitors. ACAT inhibitors enhance intracellular degradation of VLDL in hepatocytes. Cholesterol absorption in small intestine is inhibited by ACAT inhibitors. Thus, ACAT inhibitors reduce plasma cholesterol levels. In atherosclerotic lesions, ACAT inhibitors suppress foam cell formation (cholesteryl ester accumulation) in macrophages. Since ACAT inhibitors have multiple anti-atherogenic effects, they are considered future drugs controlling hypercholesterolemia and atherosclerosis. CETP inhibitors are expected to increase HDL and decrease LDL. Although the patients with CETP deficiency show high level of HDL, recent studies showed that they are not necessarily resistant to atherosclerosis. The strategy to inhibit CETP for suppressing atherosclerosis has not been established.

  9. Development of immune checkpoint inhibitors.

    Science.gov (United States)

    Kitano, Shigehisa

    2017-01-01

    Immune checkpoint inhibitors are the most striking innovation in the clinical development of immunotherapy. Monoclonal antibodies (mAbs) restore and augment the antitumor immune activities of cytotoxic T cells by mainly blocking immune checkpoint molecules on T cells or their ligands on antigen-presenting and tumor cells. Based on preclinical data, many clinical trials have demonstrated the acceptable safety profiles and efficacies of mAb in various cancers. The A first-in-class approved immune checkpoint inhibitor is ipilimumab, which is a fully humanized mAb that blocks the immunosuppressive signal by cytotoxic T-lymphocyte antigen 4. In 2011, the US Food and Drug Administration approved the use of ipilimumab for the treatment of advanced metastatic melanoma. Then, nivolumab, which is a humanized mAb that blocks programmed death-1 (PD-1), was approved for use in the treatment of advanced melanoma in 2014 and of advanced non-small-cell lung carcinoma (NSCLC) in 2015 in Japan. Pembrolizumab, which is another anti-PD-1 antibody, was approved for use in the treatment of advanced melanoma and advanced NSCLC as the first-line therapy in 2016 in Japan. Thereafter, nivolumab was also approved for use in the treatment of advanced renal cell cancer in August 2016, of Hodgkin's lymphoma in December 2016, and of head and neck cancer in March 2017 in Japan. Moreover, phase III trials of anti-PD-1 mAb and anti-PD-ligand 1 mAb for use in the treatment of cancers, such as gastric, ovarian, bladder, and esophageal cancers, are ongoing. Several clinical trials have investigated new agents, alone and in combination, for use in the treatment of various cancers. Current advances in tumor immunology have unveiled the importance of immunosuppressive cells, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, especially in a tumor microenvironment (TME). Some data from basic research in mouse models and the immunomonitoring of cancer patients

  10. Calcineurin inhibitor minimisation versus continuation of calcineurin inhibitor treatment for liver transplant recipients

    DEFF Research Database (Denmark)

    Penninga, Luit; Wettergren, Andre; Chan, An-Wen

    2012-01-01

    The therapeutic success of liver transplantation has been largely attributable to the development of effective immunosuppressive treatment regimens. In particular, calcineurin inhibitors were essential in reducing acute rejection and improving early survival. Currently, more than 90% of all liver...... transplant recipients are treated with the calcineurin inhibitor cyclosporine or tacrolimus. Unfortunately, calcineurin inhibitors cause adverse events, such as nephrotoxicity, and because of this, minimisation (reduction and withdrawal) regimens of calcineurin inhibitor have been developed and studied...

  11. Integrin Inhibitors in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Maylein C. Juan-Rivera

    2018-02-01

    Full Text Available Prostate cancer (PCa is the most frequently diagnosed cancer and the third highest cause of cancer-related deaths in men in the U.S. The development of chemotherapeutic agents that can bind PCa tumor cells with high specificity is critical in order to increase treatment effectiveness. Integrin receptors and their corresponding ligands have different expression patterns in PCa cells. They have been identified as promising targets to inhibit pathways involved in PCa progression. Currently, several compounds have proven to target specific integrins and their subunits in PCa cells. In this article, we review the role of integrins inhibitors in PCa and their potential as therapeutic targets for PCa treatments. We have discussed the following: natural compounds, monoclonal antibodies, statins, campothecins analog, aptamers, d-aminoacid, and snake venom. Recent studies have shown that their mechanisms of action result in decrease cell migration, cell invasion, cell proliferation, and metastasis of PCa cells.

  12. Protein C inhibitor (plasminogen activator inhibitor-3) and the risk of venous thrombosis

    NARCIS (Netherlands)

    Meijers, JCM; Marquart, JA; Bertina, RM; Rosendaal, FR; Bouma, Bonno N.

    Protein C inhibitor (PCI), also known as plasminogen activator inhibitor-3, is a serine proteinase inhibitor that can inhibit enzymes in blood coagulation, fibrinolysis and fertility. The role of PCI in regulating the blood coagulation mechanism is not known, as it can inhibit both procoagulant

  13. Low Plasma Cholinesterase Activities are Associated with Deficits in Spatial Orientation, Reduced Ability to Perform Basic Activities of Daily Living, and Low Body Mass Index in Patients with Progressed Alzheimer's Disease.

    Science.gov (United States)

    Dingova, Dominika; Fazekas, Tomas; Okuliarova, Petra; Strbova, Jaroslava; Kucera, Matej; Hrabovska, Anna

    2016-01-01

    Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by a central cholinergic deficit. Non-neuronal cholinergic changes are, however, described as well. Here we focused on possible changes in the activity of the plasma cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hospitalized AD patients. We analyzed plasma AChE and BChE activities with regards to age, gender, body mass index (BMI), cognitive functions, and ability to perform activities of daily living in AD patients in comparison to healthy subjects. We observed lower AChE activity and trend toward lower BChE activity in AD patients, which both correlated with low BMI. AD patients unable to perform basic activities of daily living (feeding, bathing, dressing, and grooming) showed reduced plasma AChE activities, while worse spatial orientation was linked to lower BChE activities. Three out of four AD patients with the lowest BChE activities died within one year. In conclusion, progressed AD was accompanied by lower plasma AChE activity and trend toward lower BChE activity, which correlated with BMI and deficits in different components of the AD.

  14. 2011 ANNUAL SITE ENVIRONMENTAL REPORT

    Energy Technology Data Exchange (ETDEWEB)

    Meyer, A.; Eddy, T.; Jannik, T.; Terry, B.; Cauthen, K.; Coward, L.; Dunaway-Ackerman, J.; Wilson, M.; Hutchison, J.; O' Quinn, S.

    2012-10-01

    The Savannah River Site Environmental Report for 2011 (SRNS-STI-2012-00200) is prepared for the U.S. Department of Energy (DOE) according to requirements of DOE Order 231.1 B, “Environment, Safety and Health Reporting." The annual SRS Environmental Report has been produced for more than 50 years. Several hundred copies are and interested individuals. The report’s purpose is to: present summary environmental data that characterize site environmental management performance; describe compliance status with respect to environmental standards and requirements; highlight significant programs and efforts.

  15. Annual report 1993-94

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1994-12-31

    The annual report of the Ministry presents the activities of the Ministry`s departments: Corporate (public affairs and communications, employment equity, policy, planning and legislation, management services); BC Environment (environmental protection, fisheries, wildlife and habitat protection, environment regional operations); BC Lands (lands and water management, lands regional operations, lands services, water management); BC Parks (provincial parks, ecological reserves, outdoor recreation); Agencies, Boards, and Commissions (Commission on Waste Reduction, Soils, and Hazardous Wastes, Environmental Appeal Board); and Immigration and Multiculturalism (immigration policy, business immigration, multiculturalism BC, and BC Council of Human Rights). An organizational chart and financial overview are also included.

  16. Annual reports on NMR spectroscopy

    CERN Document Server

    Webb, Graham A; McCarthy, M J

    1995-01-01

    Over recent years, no other technique has grown to such importance as that of NMR spectroscopy. It is used in all branches of science where precise structural determination is required and where the nature of interactions and reactions in solution is being studied. Annual Reports on NMR Spectroscopy has established itself as a means for the specialist and non-specialist alike to become familiar with new applications of the technique in all branches of chemistry, including biochemistry, and pharmaceutics. This volume focuses on theoretical aspects of NMR nuclear shielding and on applications of

  17. Annual review in automatic programming

    CERN Document Server

    Goodman, Richard

    2014-01-01

    Annual Review in Automatic Programming, Volume 4 is a collection of papers that deals with the GIER ALGOL compiler, a parameterized compiler based on mechanical linguistics, and the JOVIAL language. A couple of papers describes a commercial use of stacks, an IBM system, and what an ideal computer program support system should be. One paper reviews the system of compilation, the development of a more advanced language, programming techniques, machine independence, and program transfer to other machines. Another paper describes the ALGOL 60 system for the GIER machine including running ALGOL pro

  18. Annual review in automatic programming

    CERN Document Server

    Goodman, Richard

    2014-01-01

    Annual Review in Automatic Programming, Volume 2 is a collection of papers that discusses the controversy about the suitability of COBOL as a common business oriented language, and the development of different common languages for scientific computation. A couple of papers describes the use of the Genie system in numerical calculation and analyzes Mercury autocode in terms of a phrase structure language, such as in the source language, target language, the order structure of ATLAS, and the meta-syntactical language of the assembly program. Other papers explain interference or an ""intermediate

  19. Annual review in automatic programming

    CERN Document Server

    Goodman, Richard

    2014-01-01

    Annual Review in Automatic Programming focuses on the techniques of automatic programming used with digital computers. Topics covered range from the design of machine-independent programming languages to the use of recursive procedures in ALGOL 60. A multi-pass translation scheme for ALGOL 60 is described, along with some commercial source languages. The structure and use of the syntax-directed compiler is also considered.Comprised of 12 chapters, this volume begins with a discussion on the basic ideas involved in the description of a computing process as a program for a computer, expressed in

  20. Annual Report 2001; Aarsrapport 2001

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2002-07-01

    This is the annual report 2001 for the TotalFinaElf oil company. This concern operates in more than 100 countries and covers all aspects of the energy industry, from oil- and gas exploration and production to refining and marketing of refined products and international trade with both unrefined and refined products. Through the Atofina division the concern is also a major player in the chemicals markets. The demonstrated reserves of TotalFinaElf has been calculated to more than ten billion barrels of oil equivalents. At a rate of 2.1 million barrels a day this ensures 14 years of production.

  1. Annual Workshop: Higgs Couplings 2016

    CERN Document Server

    2016-01-01

    Higgs Couplings 2016 is this year's installment of an annual workshop devoted to new experimental and theoretical results on the Higgs boson. The 2016 workshop will present the latest results from the LHC run 2 on the Higgs boson mass, spin/parity, and couplings and will present new theoretical work devoted to the measurement of Higgs parameters and possibilities for exotic Higgs decays. The workshop will provide an opportunity for critical discussion of the current strategies for studying the Higgs boson at the LHC and the next steps in the LHC program. The workshop will also include discussion of the longer-term Higgs boson program at future facilities.

  2. Presentation at Innoventure Annual Competition

    Energy Technology Data Exchange (ETDEWEB)

    None

    2010-03-31

    This report documents the components of the workshop presented at the recent annual competition for the Innoventure program. The goal of the workshop was to focus on the delivery of science, technology, engineering, and math (STEM) concepts in a hands-on experiential learning format to increase interest in national security careers at NNSA, most of which are in the STEM fields. This work is a part of the National Security Preparedness Project (NSPP), being performed under a Department of Energy (DOE)/National Nuclear Security Administration (NNSA) grant.

  3. Intellectual property issues of immune checkpoint inhibitors.

    Science.gov (United States)

    Storz, Ulrich

    2016-01-01

    Immune checkpoint inhibitors are drugs that interfere with tumor escape responses. Some members of this class are already approved, and expected to be blockbusters in the future. Many companies have developed patent activities in this field. This article focuses on the patent landscape, and discusses key players and cases related to immune checkpoint inhibitors.

  4. A cyclic peptidic serine protease inhibitor

    DEFF Research Database (Denmark)

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...

  5. [Interaction between clopidogrel and proton pump inhibitors

    NARCIS (Netherlands)

    Harmsze, A.M.; Boer, A. de; Boot, H.; Deneer, V.H.; Heringa, M.; Mol, P.G.; Schalekamp, T.; Verduijn, M.M.; Verheugt, F.W.A.; Comte, M. le

    2011-01-01

    The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in

  6. Potential physiological role of plant glycosidase inhibitors

    DEFF Research Database (Denmark)

    Bellincampi, D.; Carmadella, L.; Delcour, J.A.

    2004-01-01

    Carbohydrate-active enzymes including glycosidases, transglycosidases, glycosyltransferases, polysaccharide lyases and carbohydrate esterases are responsible for the enzymatic processing of carbohydrates in plants. A number of carbohydrate-active enzymes are produced by microbial pathogens...... and insects responsible of severe crop losses. Plants have evolved proteinaceous inhibitors to modulate the activity of several of these enzymes. The continuing discovery of new inhibitors indicates that this research area is still unexplored and may lead to new exciting developments. To date, the role...... of the inhibitors is not completely understood. Here we review recent results obtained on the best characterised inhibitors, pointing to their possible biological role in vivo. Results recently obtained with plant transformation technology indicate that this class of inhibitors has potential biotechnological...

  7. LLNL NESHAPs 1996 Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    Gallegos, G.M.

    1997-01-06

    This annual report is prepared pursuant to the National Emissions Standards for Hazardous Air Pollutants (NESHAPs) 40 CFR Part 61, Subpart H; Subpart H governs radionuclide emissions to air from Department of Energy (DOE) facilities. NESHAPs limits the emission of radionuclides to the ambient air from DOE facilities to levels resulting in an annual effective dose equivalent (EDE) of 10 mrem (10 microsieverts) to any member of the public. The EDEs for the Lawrence Livermore National Laboratory (LLNL) site-wide maximally exposed members of the public from 1996 operations were (1) Livermore site: 0. 093 mrem (0.93 microsievert) (52% from point-source emissions, 48% from diffuse-source emissions); (2) Site 300: 0.033 mrem (0.33 microsievert) (99% from point-source, 1% from diffuse-source emissions). The EDEs were generally calculated using the EPA-approved CAP88-PC air-dispersion/dose-assessment model. Site-specific meteorological data, stack flow data, and emissions estimates based on radionuclide inventory data or continuous-monitoring systems data were the specific input to CAP88-PC for each modeled source. 5 figs., 8 tabs.

  8. Bifunctional compounds eliciting anti-inflammatory and anti-cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning.

    Science.gov (United States)

    Amitai, Gabi; Adani, Rachel; Fishbein, Eliezer; Meshulam, Haim; Laish, Ido; Dachir, Schlomit

    2005-12-15

    Studies cited by Cowan et al. [J. Appl. Toxicol. 23, 177 (2003)] indicate existence of inflammatory and cholinergic pathways in both nerve agents and sulfur mustard (HD) injury. Increase in AChE synthesis and neurite extension was noted after exposure to HD [K.W. Lanks et al., Exp. Cell Res. 355 (1975)]. Moreover, anti-inflammatory drugs reduce the dermal, respiratory and ocular damage caused by exposure to HD. On the other hand, recent studies have noted the involvement of neuro-inflammatory processes during exposure to the nerve agents sarin or soman [Cowan et al., 2003]. The use of various anti-inflammatory drugs in addition to the classical antidotal drugs (e.g. atropine and oximes) caused decrease in certain toxic symptoms and inflammation-induced brain damage. Our new bifunctional drugs (Scheme 1) are based on CNS-permeable molecular combination of pseudo-reversible AChE inhibitor (pyridostigmine, PYR) coupled via a hydrophobic spacer (octyl or decyl hydrocarbon chain) to a non-steroidal anti-inflammatory drug (NSAID) such as Ibuprofen or Diclofenac (Scheme 1). This study evaluates the efficacy of certain bifunctional compounds against HD and soman poisoning in mice in vivo.

  9. Galanthamine, an anti-cholinesterase drug, effects plant growth and development in Artemisia tridentata Nutt. via modulation of auxin and neurotransmitter signaling.

    Science.gov (United States)

    Turi, Christina E; Axwik, Katarina E; Smith, Anderson; Jones, A Maxwell P; Saxena, Praveen K; Murch, Susan J

    2014-01-01

    Galanthamine is a naturally occurring acetylcholinesterase (AchE) inhibitor that has been well established as a drug for treatment of mild to moderate Alzheimer disease, but the role of the compound in plant metabolism is not known. The current study was designed to investigate whether galanthamine could redirect morphogenesis of Artemisia tridentata Nutt. cultures by altering concentration of endogenous neurosignaling molecules acetylcholine (Ach), auxin (IAA), melatonin (Mel), and serotonin (5HT). Exposure of axenic A. tridentata cultures to 10 µM galanthamine decreased the concentration of endogenous Ach, IAA, MEL, and AchE, and altered plant growth in a manner reminiscent of 2-4D toxicity. Galanthamine itself demonstrated IAA activity in an oat coleoptile elongation bioassay, 20 µM galanthamine showed no significant difference compared with 5 μM IAA or 5 μM 1-Naphthaleneacetic acid (NAA). Metabolomic analysis detected between 20,921 to 27,891 compounds in A. tridentata plantlets and showed greater commonality between control and 5 µM treatments. Furthermore, metabolomic analysis putatively identified coumarins scopoletin/isoscopoletin, and scopolin in A. tridentata leaf extracts and these metabolites linearly increased in response to galanthamine treatments. Overall, these data indicate that galanthamine is an allelopathic phytochemical and support the hypothesis that neurologically active compounds in plants help ensure plant survival and adaptation to environmental challenges.

  10. Venous Thromboembolism Prophylaxis After TKA: Aspirin, Warfarin, Enoxaparin, or Factor Xa Inhibitors?

    Science.gov (United States)

    Bala, Abiram; Huddleston, James I; Goodman, Stuart B; Maloney, William J; Amanatullah, Derek F

    2017-09-01

    There is considerable debate regarding the ideal agent for venous thromboembolism (VTE) prophylaxis after TKA. Numerous studies and meta-analyses have yet to provide a clear answer and often omit one or more of the commonly used agents such as aspirin, warfarin, enoxaparin, and factor Xa inhibitors. Using a large database analysis, we asked: (1) What are the differences in VTE incidence in primary TKA after administration of aspirin, warfarin, enoxaparin, or factor Xa inhibitors? (2) What are the differences in bleeding risk among these four agents? (3) How has use of these agents changed with time? We queried a combined Humana and Medicare database between 2007 and Quarter 1 of 2016, and identified all primary TKAs performed using ICD-9 and Current Procedural Terminology codes. All patients who had any form of antiplatelet or anticoagulation prescribed within 1 year before TKA were excluded from our study cohort. We then identified patients who had either aspirin, warfarin, enoxaparin, or factor Xa inhibitors prescribed within 2 weeks of primary TKA. Each cohort was matched by age and sex. Elixhauser comorbidities and Charlson Comorbidity Index for each group were calculated. We identified 1016 patients with aspirin, and age- and sex-matched 6096 patients with enoxaparin, 6096 patients with warfarin, and 5080 patients with factor Xa inhibitors. Using ICD-9 codes, with the understanding that patients at greater risk may have had more-attentive surveillance, the incidence of postoperative deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding-related complications (bleeding requiring surgical intervention, hemorrhage, hematoma, hemarthrosis), postoperative anemia, and transfusion were identified at 2 weeks, 30 days, 6 weeks, and 90 days postoperatively. A four-way chi-squared test was used to determine statistical significance. Utilization was calculated using compound annual growth rate. There was a difference in the incidence of DVT at 90 days (p aspirin

  11. US (United States) Army Aeromedical Research Laboratory Annual Progress Report, FY 1982.

    Science.gov (United States)

    1982-10-01

    the application of epidemiologic methods, medically related engineering failure mode analysis, accident investigative procedures, forensic patholo- gy...physostigmine and DFP, and cholinesterase assays have been started to alleviate the problem. DD pot WACO REVIOU. ED.I OAS OF TIS FORM AREC ORIOLE CC

  12. AZT as a telomerase inhibitor

    Directory of Open Access Journals (Sweden)

    Daniel E Gomez

    2012-09-01

    Full Text Available Telomerase is a highly specialized reverse transcriptase and the maintenance of telomeric length is determined by this specific enzyme. The human holoenzyme telomerase is a ribonucleoprotein composed by a catalytic subunit, hTERT, an RNA component, hTR, and a group of associated proteins. Telomerase is normally expressed in embryonic cells and is repressed during adulthood. The enzyme is reexpressed in around 85% of solid tumors. This observation makes it a potential target for developing drugs that could be developed for therapeutic purposes. The identification of the hTERT as a functional catalytic reverse transcriptase prompted studies of inhibiting telomerase with the HIV reverse transcriptase inhibitor azidothymidine (AZT. Previously, we have demonstrated that AZT binds preferentially to telomeres, inhibits telomerase and enhances tumor cell senescence and apoptosis after AZT treatment in breast mammary adenocarcinoma cells. Since then, several studies have considered AZT for telomerase inhibition and have led to potential clinical strategies for anticancer therapy. This review covers present thinking of the inhibition of telomerase by AZT and future treatment protocols using the drug.

  13. ALK inhibitors, a pharmaceutical perspective

    Directory of Open Access Journals (Sweden)

    Arturo eGalvani

    2012-02-01

    Full Text Available In 2007, the ALK tyrosine kinase, already known to be translocated and activated in Anaplastic Large Cell Lymphoma, and a few other rare cancers, was described as a potential therapeutic target for a subset of non small-cell lung cancer (NSCLC patients. Clinical proof of concept, culminating in the recent approval by the FDA of the Pfizer drug Xalkori (crizotinib, formerly known as PF-02341066 followed in record time. The drug was approved together with a companion diagnostic, the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc. for detection of eligible patients. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in this rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib has already been observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy, and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may also occur through ALK-independent mechanisms, which still need to be elucidated in detail.

  14. Novel Toxoplasma gondii inhibitor chemotypes.

    Science.gov (United States)

    Sanford, A G; Schulze, T T; Potluri, L P; Hemsley, R M; Larson, J J; Judge, A K; Zach, S J; Wang, X; Charman, S A; Vennerstrom, J L; Davis, P H

    2018-04-01

    We profiled three novel T. gondii inhibitors identified from an antimalarial phenotypic high throughput screen (HTS) campaign: styryl 4-oxo-1,3-benzoxazin-4-one KG3, tetrahydrobenzo[b]pyran KG7, and benzoquinone hydrazone KG8. These compounds inhibit T. gondii in vitro with IC 50 values ranging from 0.3 to 2μM, comparable to that of 0.25 to 1.5μM for the control drug pyrimethamine. KG3 had no measurable cytotoxicity against five mammalian cell lines, whereas KG7 and KG8 inhibited the growth of 2 of 5 cell lines with KG8 being the least selective for T. gondii. None of the compounds were mutagenic in an Ames assay. Experimental gLogD 7.4 and calculated PSA values for the three compounds were well within the ranges predicted to be favorable for good ADME, even though each compound had relatively low aqueous solubility. All three compounds were metabolically unstable, especially KG3 and KG7. Multiple IP doses of 5mg/kg KG7 and KG8 increased survival in a T. gondii mouse model. Despite their liabilities, we suggest that these compounds are useful starting points for chemical prospecting, scaffold-hopping, and optimization. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Vascular calcification: Inducers and inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Donghyun, E-mail: dhlee@cau.ac.kr [Department of Biomedical Engineering, Division of Integrative Engineering, Chung-Ang University, 221 Heukseok-Dong, Dongjak-Gu, Seoul 156-756 (Korea, Republic of)

    2011-09-15

    Highlights: {center_dot} Types of vascular calcification processes. {center_dot} Inducers of vascular calcification. {center_dot} Inhibitors of vascular calcifications. {center_dot} Clinical utility for vascular calcification therapy. {center_dot} Implications for the development of new tissue engineering strategies. - Abstract: Unlike the traditional beliefs, there are mounting evidences suggesting that ectopic mineral depositions, including vascular calcification are mostly active processes, many times resembling that of the bone mineralization. Numbers of agents are involved in the differentiation of certain subpopulation of smooth muscle cells (SMCs) into the osteoblast-like entity, and the activation and initiation of extracellular matrix ossification process. On the other hand, there are factors as well, that prevent such differentiation and ectopic calcium phosphate formation. In normal physiological environments, activities of such procalcific and anticalcific regulatory factors are in harmony, prohibiting abnormal calcification from occurring. However, in certain pathophysiological conditions, such as atherosclerosis, chronic kidney disease (CKD), and diabetes, such balances are altered, resulting in abnormal ectopic mineral deposition. Understanding the factors that regulate the formation and inhibition of ectopic mineral formation would be beneficial in the development of tissue engineering strategies for prevention and/or treatment of such soft-tissue calcification. Current review focuses on the factors that seem to be clinically relevant and/or could be useful in developing future tissue regeneration strategies. Clinical utilities and implications of such factors are also discussed.

  16. Development of green vapour corrosion inhibitor

    Science.gov (United States)

    Asmara, Y. P.; Suraj, V.; Siregar, J. P.; Kurniawan, T.; Bachtiar, D.; Mohamed, N. M. Z. N.

    2017-10-01

    Corrosion control using inhibitor is an effective method to protect carbon steel from corrosion. Due to environmental toxicity of chemical inorganic corrosion inhibitors (synthetic), green inhibitors are potentially to develop. In atmospheric conditions, green vapour corrosion inhibitors are the best solutions to replace the uses of inorganic corrosion inhibitors. This research used chemical acid extraction from the key lime (citrus aurantiifolia) leaves and seeds. They are used as the main ingredients to produce this effective green corrosion inhibitor. The experiments investigated effects of corrosion inhibition on corrosion rate of low carbon steel in 3% NaCl solution using both fog salt chamber and electrochemical cell. Using salt fog chamber to represent atmospheric conditions, and corrosion rates are evaluated visually and calculated using weight loss methods. Corrosion rate on electrochemical cell were calculated using linear polarization resistance (LPR) methods. All of the experiments were set in natural conditions at pH 7. Using weight loss for three days exposure time, the efficiency of the inhibitor reached 82.39%.

  17. Histone Deacetylase Inhibitors as Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    Tomas Eckschlager

    2017-07-01

    Full Text Available Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC and histone acetyltransferases (HAT. HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  18. Histone Deacetylase Inhibitors as Anticancer Drugs.

    Science.gov (United States)

    Eckschlager, Tomas; Plch, Johana; Stiborova, Marie; Hrabeta, Jan

    2017-07-01

    Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  19. NOAA Average Annual Salinity (3-Zone)

    Data.gov (United States)

    California Department of Resources — The 3-Zone Average Annual Salinity Digital Geography is a digital spatial framework developed using geographic information system (GIS) technology. These salinity...

  20. 2008 annual CERN Road Race

    CERN Document Server

    2008-01-01

    Dear runners, The 2008 annual CERN Road Race will be held on Wednesday 24 September at 6.00 p.m. This 5.4 km race consists of 3 laps of a 1.8 km circuit in the West Area of the Meyrin site and is open to everyone working at CERN and their families. Past races have attracted runners of all speeds, with times ranging from under 17 to over 34 minutes. The race is run on a handicap basis, with starting times staggered to ensure that (in theory) all runners finish together. However, if the popularity of the race continues to grow (95 runners took part last year), its format may be modified to a classic single start. For more information and to complete the online entry form, go to http://club-running.web.cern.ch

  1. Annual report 1998-1999

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1999-07-01

    This is the Annual Report of the Atomic Energy of Canada Limited for the year ending March 31, 1999 and summarizes the activities of AECL during the period 1998-1999. The Activities covered in this Report include the CANDU Reactor Business, with excellent progress reported on the construction of two 700 MWe-class CANDU reactors in Qinshan, China. In the Republic of Korea, Wolsong Unit entered into commercial operation and Wolsong Unit 4 achieved sustained nuclear reaction. The Report also covers AECL's R and D and Waste Management programs. In the R and D section, the report outlines the development of the CANFLEX fuel bundle, Fuel Channels, Reactor Safety, Code Validation, Fuels and Fuel Cycles as well as Heavy Water production. Progress in the Waste Management program is also discussed.

  2. Annual Cycle Energy System (ACES)

    Science.gov (United States)

    Holman, A. S.; Abbatiello, L. A.

    1980-05-01

    A single family residence near Knoxville, Tennessee, is being used to demonstrate the energy conserving features of the annual cycle energy system (ACES), an integrated heating and cooling system that utilizes a unidirectional heat pump and low temperature thermal storage. A second house, the control house, is being used to compare the performance of the ACES with that of an electric resistance heating and hot water system combined with a central air conditioning system. The ACES reduced peak utility system demands significantly: a reduction from 11.7 to 3.1 kW was achieved in the winter and from 4.1 to 0.7 kW in the summer. The only problems encountered were a heat leak into the storage bin that was twice the calculated value and control logic errors that produced excessive hot water in the winter, requiring extensive use of the night heat rejection mode in the summer. These problems are currently being corrected.

  3. Laser Program annual report 1984

    Energy Technology Data Exchange (ETDEWEB)

    Rufer, M.L.; Murphy, P.W. (eds.)

    1985-06-01

    The Laser Program Annual Report is part of the continuing series of reports documenting the progress of the unclassified Laser Fusion Program at the Lawrence Livermore National Laboratory (LLNL). As in previous years, the report is organized programmatically. The first section is an overview of the basic goals and directions of the LLNL Inertial Confinement Fusion (ICF) Program, and highlights the year's important accomplishments. Sections 2 through 7 provide the detailed information on the various program elements: Laser Systems and Operations, Target Design, Target Fabrication, Laser Experiments and Advanced Diagnostics, Advanced Laser Development, and Applications of Inertial Confinement Fusion. Individual sections will be indexed separately. 589 refs., 333 figs., 25 tabs.

  4. Annual report to Congress, 1993

    Energy Technology Data Exchange (ETDEWEB)

    1994-03-31

    Created by Congress in 1977 as an independent entity within the Department of Energy, the Energy Information Administration (EIA) is the principal and authoritative source of comprehensive energy data for the Congress, the Federal Government, the States, and the public. With the mandate to ``collect, assemble, evaluate, analyze, and disseminate data and information,`` EIA`s mission has been defined to: maintain a comprehensive data and information program relevant to energy resources and reserves, energy production, energy demand, energy technologies, and related financial and statistical information relevant to the adequacy of energy resources to meet the Nation`s demands in the near and longer term future. Develop and maintain analytical tool and collection and processing systems; provide analyses that are accurate, timely, and objective; and provide information dissemination services. This annual report summarizes EIA`s activities and accomplishments in 1993.

  5. Laser program annual report 1983

    Energy Technology Data Exchange (ETDEWEB)

    Hendricks, C.D.; Rufer, M.L.; Murphy, P.W. (eds.)

    1984-06-01

    In the 1983 Laser Program Annual Report we present the accomplishments and unclassified activities of the Laser Program at Lawrence Livermore National laboratory (LLNL) for the year 1983. It should be noted that the report, of necessity, is a summary, and more detailed expositions of the research can be found in the many publications and reports authored by staff members in the Laser Program. The purpose of this report is to present our work in a brief form, but with sufficient depth to provide an overview of the analytical and experimental aspects of the LLNL Inertial-Confinement Fusion (ICF) Program. The format of this report is basically the same as that of previous years. Section 1 is an overview and highlights the important accomplishments and directions of the Program. Sections 2 through 7 provide the detailed information on the various major parts of the Program: Laser Systems and Operations, Target Design, Target Fabrication, Fusion Experiments, Laser Research and Development, and Energy Applications.

  6. LLNL NESHAPs 2014 Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, K. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Bertoldo, N. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Gallegos, G. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); MacQueen, D. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Wegrecki, A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-07-01

    Lawrence Livermore National Security, LLC operates facilities at Lawrence Livermore National Laboratory (LLNL) where radionuclides are handled and stored. These facilities are subject to the U.S. Environmental Protection Agency (EPA) National Emission Standards for Hazardous Air Pollutants (NESHAPs) in Code of Federal Regulations (CFR) Title 40, Part 61, Subpart H, which regulates radionuclide emissions to air from Department of Energy (DOE) facilities. Specifically, NESHAPs limits the emission of radionuclides to the ambient air to levels resulting in an annual effective dose equivalent of 10 mrem (100 μSv) to any member of the public. Using measured and calculated emissions, and building-specific and common parameters, LLNL personnel applied the EPA-approved computer code, CAP88-PC, Version 4.0.1.17, to calculate the dose to the maximally exposed individual member of the public for the Livermore Site and Site 300.

  7. Spine Tango annual report 2012.

    Science.gov (United States)

    Neukamp, M; Perler, G; Pigott, T; Munting, E; Aebi, M; Röder, C

    2013-09-01

    Since the Spine Tango registry was founded over a decade ago it has become established internationally. An annual report has been produced using the same format as the SWEspine group to allow for first data comparisons between the two registries. Data was captured with the latest generation of surgery and follow-up forms. Also, the Core Outcome Measures Index (COMI) from interventions performed in the year 2012 with follow-up to June 2013 was analyzed. Groups of patients with the most common degenerative lumbar spine diseases and a single group of patients with degenerative cervical spine diseases were created. The demographics, risk factors, previous treatments, current treatment, short-term outcomes, patient satisfaction and complications were analyzed. Pre- and postoperative pain and function scores were derived from the COMI. About 6,500 procedures were captured with Spine Tango in 2012. The definitions and composition of all the degenerative groups could not completely be matched between the two registries with the consequence that the age and sex distributions were partially different. Preoperative pain levels were similar. The short-term outcomes available did not allow for evaluation of the final result of surgical intervention. This will be possible with the longer term data in the next annual report. There was a distinct disparity in reported complication rates between surgeons and patients. This is a valuable first step in creating comparable reports for SWEspine and Spine Tango. The German spine registry may be able to collaborate in the future because of similar items and data structure as Spine Tango. There needs to be more work on understanding the harmonization of the different degenerative subgroups. The Spine Tango report is weakened by the short and incomplete follow-up. The visual presentation of data may be a useful model for aiding decision making for surgeons and patients in the future.

  8. FY 1996 annual work plan

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-09-30

    In April 1994, the Department of Energy (DOE) Strategic Plan was issued. This Plan presents the Department`s strategic outlook in response to a changing world. It discusses the Department`s unique capabilities; its mission, vision, and core values; and key customer and stakeholder considerations. The DOE Strategic Plan lists business strategies and critical success factors which are intended to aid the Department in accomplishing its mission and reaching its vision of itself in the future. The Office of Inspector General (OIG) has an important role in carrying out the goals and objectives of the Secretary`s Strategic Plan. The ultimate goal of the OIG is to facilitate positive change by assisting its customers, responsible Government officials, in taking actions to improve programs and operations. The Inspector General annually issues his own Strategic Plan that contains program guidance for the next fiscal year. As part of its responsibility in carrying out the OIG mission, the Office of the Deputy Inspector General for Audit Services (Office of Audit Services) publishes an Annual Work Plan that sets forth audits that are planned for the next fiscal year. Selection of these audits is based on the overall budget of the Department, analyses of trends in Departmental operations, guidance contained in the agency`s strategic plans, statutory requirements, and the expressed needs and audit suggestions of Departmental program managers and OIG managers and staff. This work plan includes audits that are carried over from FY 1995 and audits scheduled to start during FY 1996. Audits included in the plan will be performed by OIG staff.

  9. An Updated Review of Tyrosinase Inhibitors

    Directory of Open Access Journals (Sweden)

    Te-Sheng Chang

    2009-05-01

    Full Text Available Tyrosinase is a multifunctional, glycosylated, and copper-containing oxidase, which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors newly discovered from natural and synthetic sources. The inhibitory strength is compared with that of a standard inhibitor, kojic acid, and their inhibitory mechanisms are discussed.

  10. Contemporary protease inhibitors and cardiovascular risk

    DEFF Research Database (Denmark)

    Lundgren, Jens; Mocroft, Amanda; Ryom, Lene

    2018-01-01

    PURPOSE OF REVIEW: To review the evidence linking use of HIV protease inhibitors with excess risk of cardiovascular disease (CVD) in HIV+ populations. RECENT FINDINGS: For the two contemporary most frequently used protease inhibitors, darunavir and atazanavir [both pharmacologically boosted...... with ritonavir (/r)], darunavir/r has been shown to be associated with increased CVD risk. The effect is cumulative with longer exposure increasing risk and an effect size comparable to what has been observed for previously developed protease inhibitors. Biological mechanisms may be overlapping and include...... on individualization of care based on underlying risk of CVD....

  11. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice.

    Science.gov (United States)

    Gujjar, Ramesh; Marwaha, Alka; El Mazouni, Farah; White, John; White, Karen L; Creason, Sharon; Shackleford, David M; Baldwin, Jeffrey; Charman, William N; Buckner, Frederick S; Charman, Susan; Rathod, Pradipsinh K; Phillips, Margaret A

    2009-04-09

    Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.

  12. Calcineurin inhibitors in heart transplantation.

    Science.gov (United States)

    Keogh, Anne

    2004-05-01

    The use of calcineurin inhibitors (CNIs; cyclosporine and tacrolimus) has dramatically increased medium-term life expectancy after heart transplantation but has had only limited impact on long-term outcomes for heart transplant recipients. The original oil-based formulation of cyclosporine has been superceded by a microemulsion formulation (Neoral), which has more predictable pharmacokinetics and allows more precise dose-tailoring. Cyclosporine microemulsion and tacrolimus (Prograf) have a similar efficacy in the prevention of acute rejection of heart transplants, but their use is accompanied by nephrotoxicity and by cardiovascular side effects. The efficacy of immunosuppression can be improved by adjunctive therapy, such as azathioprine, mycophenolate mofetil (MMF; Cellcept), corticosteroids, and induction therapy. One of the most important predictors of patient mortality at >5 years after heart transplantation is cardiac allograft vasculopathy (CAV)/late graft failure, which accounts for 31% of deaths. Neither cyclosporine nor tacrolimus have been shown to prevent the development of CAV. In terms of efficacy, MMF provides a modest advantage over azathioprine in preventing CAV, and the combination of cyclosporine plus MMF results in significantly lower mortality than cyclosporine plus azathioprine. Overall, CNIs have multiple cardiovascular side effects, such as hypertension, hyperlipidemia and new-onset diabetes after transplantation, although cyclosporine and tacrolimus have somewhat different cardiovascular side-effect profiles. The challenge in choosing the best immunosuppressive regimen is to balance efficacy and safety to optimize graft and patient survival over the course of many decades. Because cyclosporine and tacrolimus have similar efficacy against acute rejection the choice of CNI for heart transplant recipients should be based on the relative risk of cardiovascular and renal side effects.

  13. Predicting the Performance of Organic Corrosion Inhibitors

    Directory of Open Access Journals (Sweden)

    David A. Winkler

    2017-12-01

    Full Text Available The withdrawal of effective but toxic corrosion inhibitors has provided an impetus for the discovery of new, benign organic compounds to fill that role. Concurrently, developments in the high-throughput synthesis of organic compounds, the establishment of large libraries of available chemicals, accelerated corrosion inhibition testing technologies, and the increased capability of machine learning methods have made discovery of new corrosion inhibitors much faster and cheaper than it used to be. We summarize these technical developments in the corrosion inhibition field and describe how data-driven machine learning methods can generate models linking molecular properties to corrosion inhibition that can be used to predict the performance of materials not yet synthesized or tested. We briefly summarize the literature on quantitative structure–property relationships models of small organic molecule corrosion inhibitors. The success of these models provides a paradigm for rapid discovery of novel, effective corrosion inhibitors for a range of metals and alloys in diverse environments.

  14. Kinase inhibitors for advanced medullary thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    Martin Schlumberger

    2012-01-01

    Full Text Available The recent availability of molecular targeted therapies leads to a reconsideration of the treatment strategy for patients with distant metastases from medullary thyroid carcinoma. In patients with progressive disease, treatment with kinase inhibitors should be offered.

  15. Electrochemical Behaviour of Environmentally Friendly Inhibitor of ...

    African Journals Online (AJOL)

    Electrochemical Behaviour of Environmentally Friendly Inhibitor of Aloe Secundiflora Extract in Corrosion Control of Carbon Steel in Soft Water Media. ... corrosion control in neutral and aerated soft water solutions have been investigated using electrochemical impedance spectroscopy and Tafel polarization techniques.

  16. Small-Molecule Inhibitors of Urea Transporters

    Science.gov (United States)

    Verkman, Alan S.; Esteva-Font, Cristina; Cil, Onur; Anderson, Marc O.; Li, Fei; Li, Min; Lei, Tianluo; Ren, Huiwen; Yang, Baoxue

    2015-01-01

    Urea transporter (UT) proteins, which include isoforms of UT-A in kidney tubule epithelia and UT-B in vasa recta endothelia and erythrocytes, facilitate urinary concentrating function. Inhibitors of urea transporter function have potential clinical applications as sodium-sparing diuretics, or ‘urearetics,’ in edema from different etiologies, such as congestive heart failure and cirrhosis, as well as in syndrome of inappropriate antidiuretic hormone (SIADH). High-throughput screening of drug-like small molecules has identified UT-A and UT-B inhibitors with nanomolar potency. Inhibitors have been identified with different UT-A versus UT-B selectivity profiles and putative binding sites on UT proteins. Studies in rodent models support the utility of UT inhibitors in reducing urinary concentration, though testing in clinically relevant animal models of edema has not yet been done. PMID:25298345

  17. The effect of chemical anti-inhibitors on fibrinolytic enzymes and inhibitors

    DEFF Research Database (Denmark)

    Sidelmann, Johannes Jakobsen; Jespersen, J; Kluft, C

    1997-01-01

    proteases. We studied the influence of chemical anti-inhibitors (chloramine T, flufenamate, sodium lauryl sulfate, and methylamine) on fibrinolytic serine proteases and fibrinolytic enzyme inhibitors using the physiological substrate fibrin as plasmin substrate. Low concentrations of chloramine T (0.01 mmol....../l) prevent the inhibition of plasminogen activators. Higher concentrations (1 mmol/l) reduce the inhibition of plasmin, but simultaneously quench the plasminogen activator activity. Flufenamate eliminates most fibrinolytic enzyme inhibitors, but increases the activity of plasmin (apparent recovery 140......Fibrinolytic enzyme inhibitors hamper the determination of the specific fibrinolytic serine protease activity. Reportedly, chemical anti-inhibitors eliminate the influence of fibrinolytic inhibitors, but it remains unclear to what extent they change the specific activity of fibrinolytic serine...

  18. 78 FR 68023 - Annual Wholesale Trade Survey

    Science.gov (United States)

    2013-11-13

    ... collect data covering annual sales, e- commerce sales, purchases, total operating expenses, year-end... Census Bureau will collect data covering sales, e-commerce sales, year-end inventories held inside and... offices, the Census Bureau will collect data covering annual sales, e-commerce sales, year-end inventories...

  19. 76 FR 64894 - Annual Wholesale Trade Survey

    Science.gov (United States)

    2011-10-19

    ... collect data covering annual sales, e-commerce sales, purchases, total operating expenses, year-end..., e- commerce sales, year-end inventories held inside and outside the United States, purchases, and... data covering annual sales, e-commerce sales, year-end inventories held inside and outside the United...

  20. 75 FR 63805 - Annual Wholesale Trade Survey

    Science.gov (United States)

    2010-10-18

    ... Census Bureau will collect data on annual sales, e-commerce sales, purchases, total operating expenses... wholesale distributors, the Census Bureau will collect data covering sales, e-commerce sales, year-end... manufacturers' sales branches and offices, the Census Bureau will collect data covering annual sales, e-commerce...