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Sample records for numerous prodrug approaches

  1. The Prodrug Approach: A Successful Tool for Improving Drug Solubility

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    Daniela Hartmann Jornada

    2015-12-01

    Full Text Available Prodrug design is a widely known molecular modification strategy that aims to optimize the physicochemical and pharmacological properties of drugs to improve their solubility and pharmacokinetic features and decrease their toxicity. A lack of solubility is one of the main obstacles to drug development. This review aims to describe recent advances in the improvement of solubility via the prodrug approach. The main chemical carriers and examples of successful strategies will be discussed, highlighting the advances of this field in the last ten years.

  2. Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir

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    Mitesh Patel

    2014-04-01

    Full Text Available Poor systemic concentrations of lopinavir (LPV following oral administration occur due to high cellular efflux by P-glycoprotein (P-gp and multidrug resistance-associated proteins (MRPs and extensive metabolism by CYP3A4 enzymes. In this study, amino acid prodrugs of LPV were designed and investigated for their potential to circumvent efflux processes and first pass effects. Three amino acid prodrugs were synthesized by conjugating isoleucine, tryptophan and methionine to LPV. Prodrug formation was confirmed by the LCMS/MS and NMR technique. Interaction of LPV prodrugs with efflux proteins were carried out in P-gp (MDCK-MDR1 and MRP2 (MDCK-MRP2 transfected cells. Aqueous solubility studies demonstrated that prodrugs generate higher solubility relative to LPV. Prodrugs displayed higher stability under acidic conditions and degraded significantly with rise in pH. Uptake and transport data suggested that prodrugs carry significantly lower affinity towards P-gp and MRP2 relative to LPV. Moreover, prodrugs exhibited higher liver microsomal stability relative to LPV. Hence, amino acid prodrug modification might be a viable approach for enhancing LPV absorption across intestinal epithelial and brain endothelial cells which expresses high levels of P-gp and MRP2.

  3. Improvement of buccal delivery of morphine using the prodrug approach

    DEFF Research Database (Denmark)

    Christrup, Lona Louring; Jørgensen, A.; Christensen, C.B.

    1997-01-01

    relationship to the lipophilicity of the compounds. In the in vitro studies the optimal permeation was achieved for the prodrug morphine-3-propionate having a log P value of approximately 0.7. In contrast to that optimal in vivo absorption was obtained for the prodrug morphine-3-acetate having a log P value...... Improved by using ester prodrugs with higher lipophilicity than morphine itself. However, the enzymatic stability of the prodrugs in saliva also play an important role for the overall improvement in absorption properties....

  4. Dendrimer Prodrugs

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    Soraya da Silva Santos

    2016-05-01

    Full Text Available The main objective of this review is to describe the importance of dendrimer prodrugs in the design of new drugs, presenting numerous applications of these nanocomposites in the pharmaceutical field. Therefore, the use of dendrimer prodrugs as carrier for drug delivery, to improve pharmacokinetic properties of prototype, to promote drug sustained-release, to increase selectivity and, consequently, to decrease toxicity, are just some examples of topics that have been extensively reported in the literature, especially in the last decade. The examples discussed here give a panel of the growing interest dendrimer prodrugs have been evoking in the scientific community.

  5. Enhancement of Curcumin Bioavailability Via the Prodrug Approach: Challenges and Prospects.

    Science.gov (United States)

    Ratnatilaka Na Bhuket, Pahweenvaj; El-Magboub, Asma; Haworth, Ian S; Rojsitthisak, Pornchai

    2017-06-01

    Curcumin is a natural product with many interesting pharmacological properties. However, these are offset by the particularly poor biopharmaceutical properties. The oral bioavailability of curcumin in humans is very low, mainly due to low solubility, poor stability, and extensive metabolism. This has led to multiple approaches to improve bioavailability, including administration of curcumin with metabolism inhibitors, formulation into nanoparticles, modification of the curcumin structure, and development of curcumin prodrugs. In this paper, we focus on the pharmacokinetic outcomes of these approaches. Pharmacokinetic parameters of curcumin after release from prodrugs are dependent on the linker between curcumin and the promoiety, and the release itself may depend on the physiological and enzymatic environment at the site of cleavage. This is an area in which more data are required for rational design of improved linkers. Cytotoxicity of curcumin prodrugs seems to correlate well with cellular uptake in vitro, but the in vivo relevance is uncertain. We conclude that improved experimental and theoretical models of absorption of curcumin prodrugs, development of accurate analytical methods for simultaneous measurement of plasma levels of prodrug and released curcumin, and acquisition of more pharmacokinetic data in animal models for dose prediction in humans are required to facilitate movement of curcumin prodrugs into clinical trials.

  6. Increasing oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue.

    Science.gov (United States)

    Gupta, Deepak; Varghese Gupta, Sheeba; Dahan, Arik; Tsume, Yasuhiro; Hilfinger, John; Lee, Kyung-Dall; Amidon, Gordon L

    2013-02-04

    Poor oral absorption is one of the limiting factors in utilizing the full potential of polar antiviral agents. The neuraminidase target site requires a polar chemical structure for high affinity binding, thus limiting oral efficacy of many high affinity ligands. The aim of this study was to overcome this poor oral absorption barrier, utilizing prodrug to target the apical brush border peptide transporter 1 (PEPT1). Guanidine oseltamivir carboxylate (GOCarb) is a highly active polar antiviral agent with insufficient oral bioavailability (4%) to be an effective therapeutic agent. In this report we utilize a carrier-mediated targeted prodrug approach to improve the oral absorption of GOCarb. Acyloxy(alkyl) ester based amino acid linked prodrugs were synthesized and evaluated as potential substrates of mucosal transporters, e.g., PEPT1. Prodrugs were also evaluated for their chemical and enzymatic stability. PEPT1 transport studies included [(3)H]Gly-Sar uptake inhibition in Caco-2 cells and cellular uptake experiments using HeLa cells overexpressing PEPT1. The intestinal membrane permeabilities of the selected prodrugs and the parent drug were then evaluated for epithelial cell transport across Caco-2 monolayers, and in the in situ rat intestinal jejunal perfusion model. Prodrugs exhibited a pH dependent stability with higher stability at acidic pHs. Significant inhibition of uptake (IC(50) 30-fold increase in affinity compared to GOCarb. The l-valyl prodrug exhibited significant enhancement of uptake in PEPT1/HeLa cells and compared favorably with the well-absorbed valacyclovir. Transepithelial permeability across Caco-2 monolayers showed that these amino acid prodrugs have a 2-5-fold increase in permeability as compared to the parent drug and showed that the l-valyl prodrug (P(app) = 1.7 × 10(-6) cm/s) has the potential to be rapidly transported across the epithelial cell apical membrane. Significantly, only the parent drug (GOCarb) appeared in the basolateral

  7. Antiparkinson Prodrugs

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    Laura Serafina Cerasa

    2008-01-01

    Full Text Available Parkinson`s disease (PD is a progressive, neurodegenerative disorder whichinvolves the loss of dopaminergic neurons of the substantia nigra pars compacta. Currenttherapy is essentially symptomatic, and L-Dopa (LD, the direct precursor of dopamine(DA, is the treatment of choice in more advanced stages of the disease. Substitutiontherapy with LD is, however, associated with a number of acute problems. The peripheralconversion of LD by amino acid decarboxylase (AADC to DA is responsible for thetypical gastrointestinal (nausea, emesis and cardiovascular (arrhythmia, hypotension sideeffects. To minimize the conversion to DA outside the central nervous system (CNS LD isusually given in combination with peripheral inhibitors of AADC (carbidopa andbenserazide. In spite of that, other central nervous side effects such as dyskinesia, on-offphenomenon and end-of-dose deterioration still remain. The main factors responsible forthe poor bioavailability and the wide range of inter- and intra-patient variations of plasmalevels are the drug’s physical-chemical properties: low water and lipid solubility, resultingin unfavourable partition, and the high susceptibility to chemical and enzymaticdegradation. In order to improve the bioavailability, the prodrug approach appeared to bethe most promising and some LD prodrugs have been prepared in an effort to solve theseproblems. We report here a review of progress in antiparkinson prodrugs, focusing onchemical structures mainly related to LD, DA and dopaminergic agonists.

  8. Prodrugs in Cardiovascular Therapy

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    Maryam Tabrizian

    2008-05-01

    Full Text Available Prodrugs are biologically inactive derivatives of an active drug intended to solve certain problems of the parent drug such as toxicity, instability, minimal solubility and non-targeting capabilities. The majority of drugs for cardiovascular diseases undergo firstpass metabolism, resulting in drug inactivation and generation of toxic metabolites, which makes them appealing targets for prodrug design. Since prodrugs undergo a chemical reaction to form the parent drug once inside the body, this makes them very effective in controlling the release of a variety of compounds to the targeted site. This review will provide the reader with an insight on the latest developments of prodrugs that are available for treating a variety of cardiovascular diseases. In addition, we will focus on several drug delivery methodologies that have merged with the prodrug approach to provide enhanced target specificity and controlled drug release with minimal side effects.

  9. Enhancing the intestinal membrane permeability of zanamivir: a carrier mediated prodrug approach.

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    Gupta, Sheeba Varghese; Gupta, Deepak; Sun, Jing; Dahan, Arik; Tsume, Yasuhiro; Hilfinger, John; Lee, Kyung-Dall; Amidon, Gordon L

    2011-12-05

    The purpose of this study was to improve the membrane permeability and oral absorption of the poorly permeable anti-influenza agent, zanamivir. The poor oral bioavailability is attributed to the high polarity (cLogP ∼ -5) resulting from the polar and zwitterionic nature of zanamivir. In order to improve the permeability of zanamivir, prodrugs with amino acids were developed to target the intestinal membrane transporter, hPepT1. Several acyloxy ester prodrugs of zanamivir conjugated with amino acids were synthesized and characterized. The prodrugs were evaluated for their chemical stability in buffers at various pHs and for their transport and tissue activation by enzymes. The acyloxy ester prodrugs of zanamivir were shown to competitively inhibit [(3)H]Gly-Sar uptake in Caco-2 cells (IC(50): 1.19 ± 0.33 mM for L-valyl prodrug of zanamivir). The L-valyl prodrug of zanamivir exhibited ∼3-fold higher uptake in transfected HeLa/hPepT1 cells compared to wild type HeLa cells, suggesting, at least in part, carrier mediated transport by the hPepT1 transporter. Further, enhanced transcellular permeability of prodrugs across Caco-2 monolayer compared to the parent drug (P(app) = 2.24 × 10(-6) ± 1.33 × 10(-7) cm/s for L-valyl prodrug of zanamivir), with only parent zanamivir appearing in the receiver compartment, indicates that the prodrugs exhibited both enhanced transport and activation in intestinal mucosal cells. Most significantly, several of these prodrugs exhibited high intestinal jejunal membrane permeability, similar to metoprolol, in the in situ rat intestinal perfusion system, a system highly correlated with human jejunal permeability. In summary, this mechanistic targeted prodrug strategy, to enhance oral absorption via intestinal membrane carriers such as hPepT1, followed by activation to parent drug (active pharmaceutical ingredient or API) in the mucosal cell, significantly improves the intestinal epithelial cell permeability of zanamivir and has the

  10. Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38.

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    Bala, Vaskor; Rao, Shasha; Boyd, Ben J; Prestidge, Clive A

    2013-11-28

    SN38 (7-ethyl-10-hydroxy camptothecin) is a prominent and efficacious anticancer agent. It is poorly soluble in both water and pharmaceutically approved solvents; therefore, the direct formulation of SN38 in solution form is limited. Currently, the water soluble prodrug of SN38, irinotecan (CPT-11), is formulated as a low pH solution and is approved for chemotherapy. However, CPT-11, along with most other water-soluble prodrugs shows unpredictable inter-patient conversion to SN38 in vivo, instability in the physiological environment and variable dose-related toxicities. More recently, macromolecular prodrugs (i.e. EZN-2208, IMMU-130) and nanomedicine formulations (i.e. nanoemulsions, polymeric micelles, lipid nanocapsule/nanoparticle, and liposomes) of SN38 have been investigated for improved delivery to cancer cells and tissues. Specifically, these carriers can take advantage of the EPR effect to direct drug preferentially to tumour tissues, thereby substantially improving efficacy and minimising side effects. Furthermore, oral delivery has been shown to be possible in preclinical results using nanomedicine formulations (i.e. dendrimers, lipid nanocapsules, polymeric micelles). This review summarizes the recent advances for the delivery of SN38 with a focus on macromolecular prodrugs and nanomedicines. © 2013 Elsevier B.V. All rights reserved.

  11. A prodrug approach involving in situ depot formation to achieve localized and sustained action of diclofenac after joint injection.

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    Thing, Mette; Ågårdh, Li; Larsen, Susan; Rasmussen, Rune; Pallesen, Jakob; Mertz, Nina; Kristensen, Jesper; Hansen, Martin; Østergaard, Jesper; Larsen, Claus Selch

    2014-12-01

    Long-acting nonsteroidal anti-inflammatory drug formulations for intra-articular injection might be effective in the management of joint pain and inflammation associated sports injuries and osteoarthritis. In this study, a prodrug-based delivery system was evaluated. The synthesized diclofenac ester prodrug, a weak base (pKa 7.52), has relatively high solubility at low pH (6.5 mg mL(-1) at pH 4) and much lower solubility at physiological pH (4.5 μg mL(-1) at pH 7.4) at 37°C. In biological media including 80% (v/v) human synovial fluid (SF), the prodrug was cleaved to diclofenac mediated by esterases. In situ precipitation of the prodrug was observed upon addition of a concentrated slightly acidic prodrug solution to phosphate buffer or SF at pH 7.4. The degree of supersaturation accompanying the precipitation process was more pronounced in SF than in phosphate buffer. In the rotating dialysis cell model, a slightly acidic prodrug solution was added to the donor cell containing 80% SF resulting in a continuous appearance of diclofenac in the acceptor phase for more than 43 h after an initial lag period of 8 h. Detectable amounts of prodrug were found in the rat joint up to 8 days after knee injection of the acidic prodrug solution. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  12. Prodrug encapsulated albumin nanoparticles as an alternative approach to manifest anti-proliferative effects of suicide gene therapy

    International Nuclear Information System (INIS)

    Tirkey, Bulbul; Bhushan, Bharat; Uday Kumar, S.; Gopinath, P.

    2017-01-01

    Conventional anticancer agents are associated with limited therapeutic efficacy and substantial nonspecific cytotoxicity. Thus, there is an imminent need for an alternative approach that can specifically annihilate the cancer cells with minimal side effects. Among such alternative approaches, CD::UPRT (cytosine deaminase uracil phosphoribosyl transferase) suicide gene therapy has tremendous potential due to its high efficacy. Prodrug 5-Fluorocytosine (5-FC) used in combination with CD::UPRT suicide gene suffers from limited solubility which subsequently leads to decline in therapeutic efficacy. In order to overcome this, 5-FC encapsulated bovine serum albumin nanoparticles (BSA-5-FC NPs) were prepared in this work by desolvation method. Physico-chemical characterizations studies revealed amorphous nature of BSA-5-FC NPs with uniform spherical morphology. Apart from increase in solubility, encapsulated 5-FC followed slow and sustained release profile. Suicide gene expressing stable clone of L-132 cells were adapted for investigating therapeutic potential of BSA-5-FC NPs. These nanoparticles were readily taken up by the cells in a concentration dependent manner and subsequently manifested apoptosis, which was further confirmed by morphological examination and gene expression analysis. These findings clearly illustrate that CD::UPRT suicide gene therapy can be efficiently utilized in combination with this nanosystem for improved suicide gene therapy and tumor eradication. - Highlights: • In this work, BSA-5-FC NPs has been prepared to achieve its sustained release and also facilitate its uptake by cells. • A protein based system has been realized for the first time to deliver prodrug for cancer therapy. • Physico-chemical characterizations further validate the formation of spherical, monodispersed and stable nanoparticles. • The therapeutic efficacy of BSA-5-FC NPs has been validated against CD::UPRT expressing stable cells.

  13. Prodrug encapsulated albumin nanoparticles as an alternative approach to manifest anti-proliferative effects of suicide gene therapy

    Energy Technology Data Exchange (ETDEWEB)

    Tirkey, Bulbul [Nanobiotechnology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667 (India); Bhushan, Bharat; Uday Kumar, S. [Nanobiotechnology Laboratory, Centre for Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667 (India); Gopinath, P., E-mail: pgopifnt@iitr.ernet.in [Nanobiotechnology Laboratory, Centre for Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667 (India); Nanobiotechnology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667 (India)

    2017-04-01

    Conventional anticancer agents are associated with limited therapeutic efficacy and substantial nonspecific cytotoxicity. Thus, there is an imminent need for an alternative approach that can specifically annihilate the cancer cells with minimal side effects. Among such alternative approaches, CD::UPRT (cytosine deaminase uracil phosphoribosyl transferase) suicide gene therapy has tremendous potential due to its high efficacy. Prodrug 5-Fluorocytosine (5-FC) used in combination with CD::UPRT suicide gene suffers from limited solubility which subsequently leads to decline in therapeutic efficacy. In order to overcome this, 5-FC encapsulated bovine serum albumin nanoparticles (BSA-5-FC NPs) were prepared in this work by desolvation method. Physico-chemical characterizations studies revealed amorphous nature of BSA-5-FC NPs with uniform spherical morphology. Apart from increase in solubility, encapsulated 5-FC followed slow and sustained release profile. Suicide gene expressing stable clone of L-132 cells were adapted for investigating therapeutic potential of BSA-5-FC NPs. These nanoparticles were readily taken up by the cells in a concentration dependent manner and subsequently manifested apoptosis, which was further confirmed by morphological examination and gene expression analysis. These findings clearly illustrate that CD::UPRT suicide gene therapy can be efficiently utilized in combination with this nanosystem for improved suicide gene therapy and tumor eradication. - Highlights: • In this work, BSA-5-FC NPs has been prepared to achieve its sustained release and also facilitate its uptake by cells. • A protein based system has been realized for the first time to deliver prodrug for cancer therapy. • Physico-chemical characterizations further validate the formation of spherical, monodispersed and stable nanoparticles. • The therapeutic efficacy of BSA-5-FC NPs has been validated against CD::UPRT expressing stable cells.

  14. Modern Prodrug Design for Targeted Oral Drug Delivery

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    Arik Dahan

    2014-10-01

    Full Text Available The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.

  15. Substrate mediated enzyme prodrug therapy

    DEFF Research Database (Denmark)

    Fejerskov, Betina; Jarlstad Olesen, Morten T; Zelikin, Alexander N

    2017-01-01

    Substrate mediated enzyme prodrug therapy (SMEPT) is a biomedical platform developed to perform a localized synthesis of drugs mediated by implantable biomaterials. This approach combines the benefits and at the same time offers to overcome the drawbacks for traditional pill-based drug administra......Substrate mediated enzyme prodrug therapy (SMEPT) is a biomedical platform developed to perform a localized synthesis of drugs mediated by implantable biomaterials. This approach combines the benefits and at the same time offers to overcome the drawbacks for traditional pill-based drug...

  16. Substrate mediated enzyme prodrug therapy.

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    Betina Fejerskov

    Full Text Available In this report, we detail Substrate Mediated Enzyme Prodrug Therapy (SMEPT as a novel approach in drug delivery which relies on enzyme-functionalized cell culture substrates to achieve a localized conversion of benign prodrug(s into active therapeutics with subsequent delivery to adhering cells or adjacent tissues. For proof-of-concept SMEPT, we use surface adhered micro-structured physical hydrogels based on poly(vinyl alcohol, β-glucuronidase enzyme and glucuronide prodrugs. We demonstrate enzymatic activity mediated by the assembled hydrogel samples and illustrate arms of control over rate of release of model fluorescent cargo. SMEPT was not impaired by adhering cells and afforded facile time - and dose - dependent uptake of the in situ generated fluorescent cargo by hepatic cells, HepG2. With the use of a glucuronide derivative of an anticancer drug, SN-38, SMEPT afforded a decrease in cell viability to a level similar to that achieved using parent drug. Finally, dose response was achieved using SMEPT and administration of judiciously chosen concentration of SN-38 glucuronide prodrug thus revealing external control over drug delivery using drug eluting surface. We believe that this highly adaptable concept will find use in diverse biomedical applications, specifically surface mediated drug delivery and tissue engineering.

  17. Prodrug Strategies for Paclitaxel

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    Ziyuan Meng

    2016-05-01

    Full Text Available Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective.

  18. Manipulation of P450 gene expression in tumours; a novel approach for targeted activation of bioreductive prodrugs

    International Nuclear Information System (INIS)

    Robson, T.; Yakkundi, A.; McCarthy, H.; McErlane, V.; Hughes, C.M.; Hirst, D.G.; McKeown, S.R.; Patterson, L.H.

    2003-01-01

    We are developing a gene-directed enzyme prodrug therapy (GDEPT) strategy to enhance the metabolism of a novel bioreductive drug, AQ4N. Bioreductive drugs are metabolically activated in the hypoxic cell environment allowing effective targeting of hypoxic radioresistant tumour regions. We aim to achieve additional layers of selectivity by using an X-ray inducible promoter linked to our therapeutic gene (cytochrome P450s). This strategy would enhance metabolism of the drug only within the radiation field. Furthermore, normal tissue would be unaffected as the bioreductive drug is only activated in hypoxic conditions. We have identified several human cytochrome P450s which are important for AQ4N prodrug activation, these include CYP3A4, 1A1 and 2B6. RIF1 murine tumour cells transfected with cDNA from any one of these CYPs displayed increased DNA damage and clonogenic cell kill following treatment with AQ4N under hypoxia compared to controls. We are presently testing the ability of these transfectants to enhance anti-tumour effectiveness of AQ4N in combination with radiation in vivo. We have shown that a single CYP3A4 injection using a simple non-optimized approach can increase metabolism of AQ4N and when used in combination with radiation 3 out of 4 tumours are locally controlled for > 60 days (McCarthy et al., 2002). This result is remarkable considering the large enhancement of the radiation effect achieved by adding AQ4N alone. This implies that the bioreduction of AQ4N by CYPs in this tumour system is sub-optimal and this strategy could therefore be very promising for clinical use where CYP levels are known to be variable. We are now exploring the CYP/AQ4N GDEPT strategy in combination with cyclophosphamide, which is also metabolised by CYPs and aim to link these CYPs to the radiation and hypoxia inducible WAF1 promoter for selective activation in vivo

  19. Long-Acting Diclofenac Ester Prodrugs for Joint Injection

    DEFF Research Database (Denmark)

    Mertz, Nina; Larsen, Susan Weng; Kristensen, Jesper

    2016-01-01

    A prodrug approach for local and sustained diclofenac action after injection into joints based on ester prodrugs having a pH-dependent solubility is presented. Inherent ester prodrug properties influencing the duration of action include their pH-dependent solubility and charge state, as well...... as susceptibility to undergo esterase facilitated hydrolysis. In this study, physicochemical properties and pH rate profiles of 3 diclofenac ester prodrugs differing with respect to the spacer carbon chain length between the drug and the imidazole-based promoiety were determined and a rate equation for prodrug...... degradation in aqueous solution in the pH range 1-10 was derived. In the pH range 6-10, the prodrugs were subject to parallel degradation to yield diclofenac and an indolinone derivative. The prodrug degradation was found to be about 6-fold faster in 80% (vol/vol) human plasma as compared to 80% (vol...

  20. A Prodrug Approach Involving In Situ Depot Formation to Achieve Localized and Sustained Action of Diclofenac After Joint Injection

    DEFF Research Database (Denmark)

    Thing, Mette; Agårdh, Li; Larsen, Susan

    2014-01-01

    Long-acting nonsteroidal anti-inflammatory drug formulations for intra-articular injection might be effective in the management of joint pain and inflammation associated sports injuries and osteoarthritis. In this study, a prodrug-based delivery system was evaluated. The synthesized diclofenac...

  1. Model prodrugs for the intestinal peptide transporter. a synthetic approach for coupling of hydroxy-containing compounds to dieptides

    DEFF Research Database (Denmark)

    Friedrichsen, G; Nielsen, Carsten Uhd; Steffansen, Bente

    2001-01-01

    The human peptide transporter, hPepT1, situated in the small intestine, may be exploited to increase absorption of drugs or model drugs by attaching them to a dipeptide, which is recognised by hPepT1. A synthetic protocol for this kind of model prodrugs was developed, in which model drugs...

  2. Targeted enzyme prodrug therapies.

    Science.gov (United States)

    Schellmann, N; Deckert, P M; Bachran, D; Fuchs, H; Bachran, C

    2010-09-01

    The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.

  3. Photoactivatable Caged Prodrugs of VEGFR-2 Kinase Inhibitors

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    Boris Pinchuk

    2016-04-01

    Full Text Available In this study, we report on the design, synthesis, photokinetic properties and in vitro evaluation of photoactivatable caged prodrugs for the receptor tyrosine kinase VEGFR-2. Highly potent VEGFR-2 inhibitors 1 and 3 were caged by introduction of a photoremovable protecting group (PPG to yield the caged prodrugs 4 and 5. As expected, enzymatic and cellular proliferation assays showed dramatically diminished efficacy of caged prodrugs in vitro. Upon ultraviolet (UV irradiation of the prodrugs original inhibitory activity was completely restored and even distinctly reinforced, as was the case for the prodrug 4. The presented results are a further evidence for caging technique being an interesting approach in the protein kinase field. It could enable spatial and temporal control for the inhibition of VEGFR-2. The described photoactivatable prodrugs might be highly useful as biological probes for studying the VEGFR-2 signal transduction.

  4. Enhancing the intestinal absorption of molecules containing the polar guanidino functionality: a double-targeted prodrug approach.

    Science.gov (United States)

    Sun, Jing; Dahan, Arik; Amidon, Gordon L

    2010-01-28

    A prodrug strategy was applied to guanidino-containing analogues to increase oral absorption via hPEPT1 and hVACVase. l-Valine, l-isoleucine, and l-phenylalanine esters of [3-(hydroxymethyl)phenyl]guanidine (3-HPG) were synthesized and evaluated for transport and activation. In HeLa/hPEPT1 cells, Val-3-HPG and Ile-3-HPG exhibited high affinity to hPEPT1 (IC(50): 0.65 and 0.63 mM, respectively), and all three l-amino acid esters showed higher uptake (2.6- to 9-fold) than the parent compound 3-HPG. Val-3-HPG and Ile-3-HPG demonstrated remarkable Caco-2 permeability enhancement, and Val-3-HPG exhibited comparable permeability to valacyclovir. In rat perfusion studies, Val-3-HPG and Ile-3-HPG permeabilities were significantly higher than 3-HPG and exceeded/matched the high-permeability standard metoprolol, respectively. All the l-amino acid 3-HPG esters were effectively activated in HeLa and Caco-2 cell homogenates and were found to be good substrates of hVACVase (k(cat)/K(m) in mM(-1) x s(-1): Val-3-HPG, 3370; Ile-3-HPG, 1580; Phe-3-HPG, 1660). In conclusion, a prodrug strategy is effective at increasing the intestinal permeability of polar guanidino analogues via targeting hPEPT1 for transport and hVACVase for activation.

  5. Multilevel Monte Carlo Approaches for Numerical Homogenization

    KAUST Repository

    Efendiev, Yalchin R.

    2015-10-01

    In this article, we study the application of multilevel Monte Carlo (MLMC) approaches to numerical random homogenization. Our objective is to compute the expectation of some functionals of the homogenized coefficients, or of the homogenized solutions. This is accomplished within MLMC by considering different sizes of representative volumes (RVEs). Many inexpensive computations with the smallest RVE size are combined with fewer expensive computations performed on larger RVEs. Likewise, when it comes to homogenized solutions, different levels of coarse-grid meshes are used to solve the homogenized equation. We show that, by carefully selecting the number of realizations at each level, we can achieve a speed-up in the computations in comparison to a standard Monte Carlo method. Numerical results are presented for both one-dimensional and two-dimensional test-cases that illustrate the efficiency of the approach.

  6. Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine.

    Science.gov (United States)

    Tsume, Yasuhiro; Drelich, Adam J; Smith, David E; Amidon, Gordon L

    2017-08-10

    One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine. The activation of all gemcitabine prodrugs was faster in pancreatic cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. All prodrugs exhibited great stability in HFF cell homogenate, enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase, and deamination by cytidine deaminase compared to their parent drug. All gemcitabine prodrugs exhibited higher uptake in HFF cells and better permeability across HFF monolayers than gemcitabine, suggesting a better delivery to tumor sites. Cell antiproliferative assays in Panc-1 and Capan-2 pancreatic ductal cell lines indicated that the gemcitabine prodrugs were more potent than their parent drug gemcitabine. The transport and enzymatic profiles of gemcitabine prodrugs suggest their potential for delayed enzymatic bioconversion and enhanced resistance to metabolic enzymes, as well as for enhanced drug delivery to tumor sites, and cytotoxic activity in cancer cells. These attributes would facilitate the prolonged systemic circulation and improved therapeutic efficacy of gemcitabine prodrugs.

  7. Numerical approach of the quantum circuit theory

    International Nuclear Information System (INIS)

    Silva, J.J.B.; Duarte-Filho, G.C.; Almeida, F.A.G.

    2017-01-01

    In this paper we develop a numerical method based on the quantum circuit theory to approach the coherent electronic transport in a network of quantum dots connected with arbitrary topology. The algorithm was employed in a circuit formed by quantum dots connected each other in a shape of a linear chain (associations in series), and of a ring (associations in series, and in parallel). For both systems we compute two current observables: conductance and shot noise power. We find an excellent agreement between our numerical results and the ones found in the literature. Moreover, we analyze the algorithm efficiency for a chain of quantum dots, where the mean processing time exhibits a linear dependence with the number of quantum dots in the array.

  8. Numerical approach of the quantum circuit theory

    Science.gov (United States)

    Silva, J. J. B.; Duarte-Filho, G. C.; Almeida, F. A. G.

    2017-03-01

    In this paper we develop a numerical method based on the quantum circuit theory to approach the coherent electronic transport in a network of quantum dots connected with arbitrary topology. The algorithm was employed in a circuit formed by quantum dots connected each other in a shape of a linear chain (associations in series), and of a ring (associations in series, and in parallel). For both systems we compute two current observables: conductance and shot noise power. We find an excellent agreement between our numerical results and the ones found in the literature. Moreover, we analyze the algorithm efficiency for a chain of quantum dots, where the mean processing time exhibits a linear dependence with the number of quantum dots in the array.

  9. Numerical approach of the quantum circuit theory

    Energy Technology Data Exchange (ETDEWEB)

    Silva, J.J.B., E-mail: jaedsonfisica@hotmail.com; Duarte-Filho, G.C.; Almeida, F.A.G.

    2017-03-15

    In this paper we develop a numerical method based on the quantum circuit theory to approach the coherent electronic transport in a network of quantum dots connected with arbitrary topology. The algorithm was employed in a circuit formed by quantum dots connected each other in a shape of a linear chain (associations in series), and of a ring (associations in series, and in parallel). For both systems we compute two current observables: conductance and shot noise power. We find an excellent agreement between our numerical results and the ones found in the literature. Moreover, we analyze the algorithm efficiency for a chain of quantum dots, where the mean processing time exhibits a linear dependence with the number of quantum dots in the array.

  10. Activation of multiple chemotherapeutic prodrugs by the natural enzymolome of tumour-localised probiotic bacteria.

    Science.gov (United States)

    Lehouritis, Panos; Stanton, Michael; McCarthy, Florence O; Jeavons, Matthieu; Tangney, Mark

    2016-01-28

    Some chemotherapeutic drugs (prodrugs) require activation by an enzyme for efficacy. We and others have demonstrated the ability of probiotic bacteria to grow specifically within solid tumours following systemic administration, and we hypothesised that the natural enzymatic activity of these tumour-localised bacteria may be suitable for activation of certain such chemotherapeutic drugs. Several wild-type probiotic bacteria; Escherichia coli Nissle, Bifidobacterium breve, Lactococcus lactis and Lactobacillus species, were screened against a panel of popular prodrugs. All strains were capable of activating at least one prodrug. E. coli Nissle 1917 was selected for further studies because of its ability to activate numerous prodrugs and its resistance to prodrug toxicity. HPLC data confirmed biochemical transformation of prodrugs to their toxic counterparts. Further analysis demonstrated that different enzymes can complement prodrug activation, while simultaneous activation of multiple prodrugs (CB1954, 5-FC, AQ4N and Fludarabine phosphate) by E. coli was confirmed, resulting in significant efficacy improvement. Experiments in mice harbouring murine tumours validated in vitro findings, with significant reduction in tumour growth and increase in survival of mice treated with probiotic bacteria and a combination of prodrugs. These findings demonstrate the ability of probiotic bacteria, without the requirement for genetic modification, to enable high-level activation of multiple prodrugs specifically at the site of action. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. The Effect of 5-Aminolevulinic Acid on Cytochrome P450-Mediated Prodrug Activation.

    Directory of Open Access Journals (Sweden)

    Mai Miura

    Full Text Available Of late, numerous prodrugs are widely used for therapy. The hemeprotein cytochrome P450 (CYP catalyzes the activation of prodrugs to form active metabolites. Therefore, the activation of CYP function might allow the use of lower doses of prodrugs and decrease toxicity. We hypothesized that the addition of 5-aminolevulinic acid (ALA, a precursor in the porphyrin biosynthetic pathway, enhances the synthesis of heme, leading to the up-regulation of CYP activity. To test this hypothesis, we treated a human gastric cancer cell line with ALA and determined the effect on CYP-dependent prodrug activation. For this purpose, we focused on the anticancer prodrug tegafur, which is converted to its active metabolite 5-fluorouracil (5-FU mainly by CYP2A6. We show here that ALA increased CYP2A6-dependent tegafur activation, suggesting that ALA elevated CYP activity and potentiated the activation of the prodrug.

  12. Pharmacological Evaluation and Preliminary Pharmacokinetics Studies of a New Diclofenac Prodrug without Gastric Ulceration Effect

    OpenAIRE

    dos Santos, Jean Leandro [UNESP; Moreira, Vanessa; Campos, Michel Leandro [UNESP; Chelucci, Rafael Consolin [UNESP; Barbieri, Karina Pereira [UNESP; Maggio de Castro Souto, Pollyana Cristina; Matsubara, Marcio Hideki; Teixeira, Catarina; Bosquesi, Priscila Longhin [UNESP; Peccinini, Rosangela Goncalves [UNESP; Chin, Chung Man [UNESP

    2012-01-01

    Long-term nonsteroidal anti-inflammatory drugs (NSAIDs) therapy has been associated with several adverse effects such as gastric ulceration and cardiovascular events. Among the molecular modifications strategies, the prodrug approach is a useful tool to discover new safe NSAIDs. The 1-(2,6-dichlorophenyl)indolin-2-one is a diclofenac prodrug which demonstrated relevant anti-inflammatory properties without gastro ulceration effect. In addition, the prodrug decreases PGE(2) levels, COX-2 expres...

  13. Numerical approach to one-loop integrals

    International Nuclear Information System (INIS)

    Fujimoto, Junpei; Shimizu, Yoshimitsu; Kato, Kiyoshi; Oyanagi, Yoshio.

    1992-01-01

    Two numerical methods are proposed for the calculation of one-loop scalar integrals. In the first method, the singularity is cancelled by the symmetrization of the integrand and the integration is done by a Monte-Carlo method. In the second one, after the transform of the integrand into a standard form, the integral is reduced into a regular numerical integral. These methods provide us practical tools to evaluate one-loop Feynman diagrams with desired numerical accuracy. They are extended to the integral with numerator and the treatment of the one-loop virtual correction to the cross section is also presented. (author)

  14. A novel numerical approach for workspace determination of parallel mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Yiqun; Niu, Junchuan; Liu, Zhihui; Zhang, Fuliang [Shandong University, Shandong (China)

    2017-06-15

    In this paper, a novel numerical approach is proposed for workspace determination of parallel mechanisms. Compared with the classical numerical approaches, this presented approach discretizes both location and orientation of the mechanism simultaneously, not only one of the two. This technique makes the presented numerical approach applicable in determining almost all types of workspaces, while traditional numerical approaches are only applicable in determining the constant orientation workspace and orientation workspace. The presented approach and its steps to determine the inclusive orientation workspace and total orientation workspace are described in detail. A lower-mobility parallel mechanism and a six-degrees-of-freedom Stewart platform are set as examples, the workspaces of these mechanisms are estimated and visualized by the proposed numerical approach. Furthermore, the efficiency of the presented approach is discussed. The examples show that the presented approach is applicable in determining the inclusive orientation workspace and total orientation workspace of parallel mechanisms with high efficiency.

  15. Numerical modelling approach for mine backfill

    Indian Academy of Sciences (India)

    Muhammad Zaka Emad

    2017-07-24

    Jul 24, 2017 ... conditions. This paper discusses a numerical modelling strategy for modelling mine backfill material. The .... placed in an ore pass that leads the ore to the ore bin and crusher, from ... 1 year, depending on the mine plan.

  16. Cytomegalovirus protease targeted prodrug development.

    Science.gov (United States)

    Sabit, Hairat; Dahan, Arik; Sun, Jing; Provoda, Chester J; Lee, Kyung-Dall; Hilfinger, John H; Amidon, Gordon L

    2013-04-01

    Human cytomegalovirus (HCMV) is a prevalent virus that infects up to 90% of the population. The goal of this research is to determine if small molecular prodrug substrates can be developed for a specific HCMV encoded protease and thus achieve site-specific activation. HCMV encodes a 256 amino acid serine protease that is responsible for capsid assembly, an essential process for herpes virus production. The esterase activity of the more stable HCMV A143T/A144T protease mutant was evaluated with model p-nitrophenol (ONp) esters, Boc-Xaa-ONp (Ala, Leu, Ile, Val, Gln, Phe at the Xaa position). We demonstrate that the A143T/A144T mutant has esterase activity toward specific small ester compounds, e.g., Boc-L-Ala-ONp. Mono amino acid and dipeptide prodrugs of ganciclovir (GCV) were also synthesized and evaluated for hydrolysis by the A143T/A144T protease mutant in solution. Hydrolysis of these prodrugs was also evaluated in Caco-2 cell homogenates, human liver microsomes (HLMs), and rat and human plasma. For the selectivity potential of the prodrugs, the hydrolysis ratio was evaluated as a percentage of prodrug hydrolyzed by the HCMV protease over the percentages of prodrug hydrolyses by Caco-2 cell homogenates, HLMs, and human/rat plasma. A dipeptide prodrug of ganciclovir, Ac-l-Gln-l-Ala-GCV, emerged as a potential selective prodrug candidate. The results of this research demonstrate that targeting prodrugs for activation by a specific protease encoded by the infectious HCMV pathogen may be achievable.

  17. Ketobemidone prodrugs for buccal delivery

    DEFF Research Database (Denmark)

    Hansen, L.B.; Christrup, Lona Louring; Bundgaard, H.

    1992-01-01

    As part of studies aiming at developing a ketobemidone prodrug suitable for buccal or sublingual administration, the potential impact of saliva enzyme-catalyzed hydrolysis of various ester prodrugs was assessed. The hydrolysis of three ketobemidone esters in human whole saliva, obtained under con...... in the mouth and their rate of disintegration were shown to have some influence on the rate of saliva secretion and hence on saliva esterase activity but not to an extent compromising the efficient buccal or sublingual delivery of the ketobemidone prodrugs....

  18. Advanced Prodrug Strategies in Nucleoside and Non-Nucleoside Antiviral Agents: A Review of the Recent Five Years

    Directory of Open Access Journals (Sweden)

    Hanadi Sinokrot

    2017-10-01

    Full Text Available Background: Poor pharmacokinetic profiles and resistance are the main two drawbacks from which currently used antiviral agents suffer, thus make them excellent targets for research, especially in the presence of viral pandemics such as HIV and hepatitis C. Methods: The strategies employed in the studies covered in this review were sorted by the type of drug synthesized into ester prodrugs, targeted delivery prodrugs, macromolecular prodrugs, other nucleoside conjugates, and non-nucleoside drugs. Results: Utilizing the ester prodrug approach a novel isopropyl ester prodrug was found to be potent HIV integrase inhibitor. Further, employing the targeted delivery prodrug zanamivir and valine ester prodrug was made and shown a sole delivery of zanamivir. Additionally, VivaGel, a dendrimer macromolecular prodrug, was found to be very efficient and is now undergoing clinical trials. Conclusions: Of all the strategies employed (ester, targeted delivery, macromolecular, protides and nucleoside analogues, and non-nucleoside analogues prodrugs, the most promising are nucleoside analogues and macromolecular prodrugs. The macromolecular prodrug VivaGel works by two mechanisms: envelope mediated and receptor mediated disruption. Nucleotide analogues have witnessed productive era in the recent past few years. The era of non-interferon based treatment of hepatitis (through direct inhibitors of NS5A has dawned.

  19. Susy theories and QCD: numerical approaches

    International Nuclear Information System (INIS)

    Ita, Harald

    2011-01-01

    We review on-shell and unitarity methods and discuss their application to precision predictions for Large Hadron Collider (LHC) physics. Being universal and numerically robust, these methods are straightforward to automate for next-to-leading-order computations within standard model and beyond. Several state-of-the-art results including studies of (W/Z+3)-jet and (W+4)-jet production have explicitly demonstrated the effectiveness of the unitarity method for describing multi-parton scattering. Here we review central ideas needed to obtain efficient numerical implementations. This includes on-shell loop-level recursions, the unitarity method, color management and further refined tricks. (review)

  20. Ducted wind turbine optimization : A numerical approach

    NARCIS (Netherlands)

    Dighe, V.V.; De Oliveira Andrade, G.L.; van Bussel, G.J.W.

    2017-01-01

    The practice of ducting wind turbines has shown a beneficial effect on the overall performance, when compared to an open turbine of the same rotor diameter1. However, an optimization study specifically for ducted wind turbines (DWT’s) is missing or incomplete. This work focuses on a numerical

  1. Long-Acting Diclofenac Ester Prodrugs for Joint Injection: Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension.

    Science.gov (United States)

    Mertz, Nina; Larsen, Susan Weng; Kristensen, Jesper; Østergaard, Jesper; Larsen, Claus

    2016-10-01

    A prodrug approach for local and sustained diclofenac action after injection into joints based on ester prodrugs having a pH-dependent solubility is presented. Inherent ester prodrug properties influencing the duration of action include their pH-dependent solubility and charge state, as well as susceptibility to undergo esterase facilitated hydrolysis. In this study, physicochemical properties and pH rate profiles of 3 diclofenac ester prodrugs differing with respect to the spacer carbon chain length between the drug and the imidazole-based promoiety were determined and a rate equation for prodrug degradation in aqueous solution in the pH range 1-10 was derived. In the pH range 6-10, the prodrugs were subject to parallel degradation to yield diclofenac and an indolinone derivative. The prodrug degradation was found to be about 6-fold faster in 80% (vol/vol) human plasma as compared to 80% (vol/vol) human synovial fluid with 2-(1-methyl-1H-imidazol-2-yl)ethyl 2-(2-(2,6 dichlorophenyl)amino)phenylacetate being the poorest substrate toward enzymatic cleavage. The conversion and release of parent diclofenac from prodrug suspensions in vitro were studied using the rotating dialysis model. The results suggest that it is possible to alter and control dissolution and reconversion behavior of the diclofenac prodrugs, thus making the prodrug approach feasible for local and sustained diclofenac action after joint injection. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  2. Prodrug Strategy in Drug Development

    Directory of Open Access Journals (Sweden)

    Hajnal Kelemen

    2016-09-01

    Full Text Available Prodrugs are chemically modified derivatives introduced in therapy due to their advantageous physico-chemical properties (greater stability, improved solubility, increased permeability, used in inactive form. Biological effect is exerted by the active derivatives formed in organism through chemical transformation (biotransformation. Currently, 10% of pharmaceutical products are used as prodrugs, nearly half of them being converted to active form by hydrolysis, mainly by ester hydrolysis. The use of prodrugs aims to improve the bioavailability of compounds in order to resolve some unfavorable characteristics and to reduce first-pass metabolism. Other objectives are to increase drug absorption, to extend duration of action or to achieve a better tissue/organ selective transport in case of non-oral drug delivery forms. Prodrugs can be characterized by chemical structure, activation mechanism or through the presence of certain functional groups suitable for their preparation. Currently we distinguish in therapy traditional prodrugs prepared by chemical derivatisation, bioprecursors and targeted delivery systems. The present article is a review regarding the introduction and applications of prodrug design in various areas of drug development.

  3. Numerical homogenization on approach for stokesian suspensions.

    Energy Technology Data Exchange (ETDEWEB)

    Haines, B. M.; Berlyand, L. V.; Karpeev, D. A. (Mathematics and Computer Science); (Department of Mathematics, Pennsylvania State Univ.)

    2012-01-20

    In this technical report we investigate efficient methods for numerical simulation of active suspensions. The prototypical system is a suspension of swimming bacteria in a Newtonian fluid. Rheological and other macroscopic properties of such suspensions can differ dramatically from the same properties of the suspending fluid alone or of suspensions of similar but inactive particles. Elongated bacteria, such as E. coli or B. subtilis, swim along their principal axis, propelling themselves with the help of flagella, attached at the anterior of the organism and pushing it forward in the manner of a propeller. They interact hydrodynamically with the surrounding fluid and, because of their asymmetrical shape, have the propensity to align with the local flow. This, along with the dipolar nature of bacteria (the two forces a bacterium exerts on a fluid - one due to self-propulsion and the other opposing drag - have equal magnitude and point in opposite directions), causes nearby bacteria to tend to align, resulting in a intermittent local ordering on the mesoscopic scale, which is between the microscopic scale of an individual bacterium and the macroscopic scale of the suspension (e.g., its container). The local ordering is sometimes called a collective mode or collective swimming. Thanks to self-propulsion, collective modes inject momentum into the fluid in a coherent way. This enhances the local strain rate without changing the macroscopic stress applied at the boundary of the container. The macroscopic effective viscosity of the suspension is defined roughly as the ratio of the applied stress to the bulk strain rate. If local alignment and therefore local strain-rate enhancement, are significant, the effective viscosity can be appreciably lower than that of the corresponding passive suspension or even of the surrounding fluid alone. Indeed, a sevenfold decrease in the effective viscosity was observed in experiments with B. subtilis. More generally, local collective

  4. Chemical and enzymatic stability of amino acid prodrugs containing methoxy, ethoxy and propylene glycol linkers.

    Science.gov (United States)

    Gupta, Deepak; Gupta, Sheeba Varghese; Lee, Kyung-Dall; Amidon, Gordon L

    2009-01-01

    linker were the least stable while prodrugs containing propylene glycol linker were most stable. This work suggests that the propylene glycol linker is an optimal linker for amino acid prodrugs since it has good chemical stability and is enzymatically hydrolyzed to yield the parent drug. This approach can be further extended to other non-amino acid prodrugs and to provide a chemical handle to modify lead molecules containing carboxylic group(s).

  5. The numerical multiconfiguration self-consistent field approach for atoms

    International Nuclear Information System (INIS)

    Stiehler, Johannes

    1995-12-01

    The dissertation uses the Multiconfiguration Self-Consistent Field Approach to specify the electronic wave function of N electron atoms in a static electrical field. It presents numerical approaches to describe the wave functions and introduces new methods to compute the numerical Fock equations. Based on results computed with an implemented computer program the universal application, flexibility and high numerical precision of the presented approach is shown. RHF results and for the first time MCSCF results for polarizabilities and hyperpolarizabilities of various states of the atoms He to Kr are discussed. In addition, an application to interpret a plasma spectrum of gallium is presented. (orig.)

  6. Substrate-Competitive Activity-Based Profiling of Ester Prodrug Activating Enzymes.

    Science.gov (United States)

    Xu, Hao; Majmudar, Jaimeen D; Davda, Dahvid; Ghanakota, Phani; Kim, Ki H; Carlson, Heather A; Showalter, Hollis D; Martin, Brent R; Amidon, Gordon L

    2015-09-08

    Understanding the mechanistic basis of prodrug delivery and activation is critical for establishing species-specific prodrug sensitivities necessary for evaluating preclinical animal models and potential drug-drug interactions. Despite significant adoption of prodrug methodologies for enhanced pharmacokinetics, functional annotation of prodrug activating enzymes is laborious and often unaddressed. Activity-based protein profiling (ABPP) describes an emerging chemoproteomic approach to assay active site occupancy within a mechanistically similar enzyme class in native proteomes. The serine hydrolase enzyme family is broadly reactive with reporter-linked fluorophosphonates, which have shown to provide a mechanism-based covalent labeling strategy to assay the activation state and active site occupancy of cellular serine amidases, esterases, and thioesterases. Here we describe a modified ABPP approach using direct substrate competition to identify activating enzymes for an ethyl ester prodrug, the influenza neuraminidase inhibitor oseltamivir. Substrate-competitive ABPP analysis identified carboxylesterase 1 (CES1) as an oseltamivir-activating enzyme in intestinal cell homogenates. Saturating concentrations of oseltamivir lead to a four-fold reduction in the observed rate constant for CES1 inactivation by fluorophosphonates. WWL50, a reported carbamate inhibitor of mouse CES1, blocked oseltamivir hydrolysis activity in human cell homogenates, confirming CES1 is the primary prodrug activating enzyme for oseltamivir in human liver and intestinal cell lines. The related carbamate inhibitor WWL79 inhibited mouse but not human CES1, providing a series of probes for analyzing prodrug activation mechanisms in different preclinical models. Overall, we present a substrate-competitive activity-based profiling approach for broadly surveying candidate prodrug hydrolyzing enzymes and outline the kinetic parameters for activating enzyme discovery, ester prodrug design, and

  7. Pharmacological evaluation and preliminary pharmacokinetics studies of a new diclofenac prodrug without gastric ulceration effect.

    Science.gov (United States)

    Santos, Jean Leandro Dos; Moreira, Vanessa; Campos, Michel Leandro; Chelucci, Rafael Consolin; Barbieri, Karina Pereira; de Castro Souto, Pollyana Cristina Maggio; Matsubara, Márcio Hideki; Teixeira, Catarina; Bosquesi, Priscila Longhin; Peccinini, Rosângela Gonçalves; Chin, Chung Man

    2012-11-19

    Long-term nonsteroidal anti-inflammatory drugs (NSAIDs) therapy has been associated with several adverse effects such as gastric ulceration and cardiovascular events. Among the molecular modifications strategies, the prodrug approach is a useful tool to discover new safe NSAIDs. The 1-(2,6-dichlorophenyl)indolin-2-one is a diclofenac prodrug which demonstrated relevant anti-inflammatory properties without gastro ulceration effect. In addition, the prodrug decreases PGE(2) levels, COX-2 expression and cellular influx into peritoneal cavity induced by carrageenan treatment. Preliminary pharmacokinetic studies have shown in vivo bioconversion of prodrug to diclofenac. This prodrug is a new nonulcerogenic NSAID useful to treat inflammatory events by long-term therapy.

  8. Pharmacological Evaluation and Preliminary Pharmacokinetics Studies of a New Diclofenac Prodrug without Gastric Ulceration Effect

    Directory of Open Access Journals (Sweden)

    Chung Man Chin

    2012-11-01

    Full Text Available Long-term nonsteroidal anti-inflammatory drugs (NSAIDs therapy has been associated with several adverse effects such as gastric ulceration and cardiovascular events. Among the molecular modifications strategies, the prodrug approach is a useful tool to discover new safe NSAIDs. The 1-(2,6-dichlorophenylindolin-2-one is a diclofenac prodrug which demonstrated relevant anti-inflammatory properties without gastro ulceration effect. In addition, the prodrug decreases PGE2 levels, COX-2 expression and cellular influx into peritoneal cavity induced by carrageenan treatment. Preliminary pharmacokinetic studies have shown in vivo bioconversion of prodrug to diclofenac. This prodrug is a new nonulcerogenic NSAID useful to treat inflammatory events by long-term therapy.

  9. Prodrugs as self-assembled hydrogels: a new paradigm for biomaterials.

    Science.gov (United States)

    Vemula, Praveen Kumar; Wiradharma, Nikken; Ankrum, James A; Miranda, Oscar R; John, George; Karp, Jeffrey M

    2013-12-01

    Prodrug-based self-assembled hydrogels represent a new class of active biomaterials that can be harnessed for medical applications, in particular the design of stimuli responsive drug delivery devices. In this approach, a promoiety is chemically conjugated to a known-drug to generate an amphiphilic prodrug that is capable of forming self-assembled hydrogels. Prodrug-based self-assembled hydrogels are advantageous as they alter the solubility of the drug, enhance drug loading, and eliminate the use of harmful excipients. In addition, self-assembled prodrug hydrogels can be designed to undergo controlled drug release or tailored degradation in response to biological cues. Herein we review the development of prodrug-based self-assembled hydrogels as an emerging class of biomaterials that overcome several common limitations encountered in conventional drug delivery. Published by Elsevier Ltd.

  10. Preclinical studies of dendrimer prodrugs.

    Science.gov (United States)

    Kojima, Chie

    2015-01-01

    Dendrimers are synthetic macromolecules with well-defined structures bearing a wide variety of functional groups on their periphery. These groups can be used to conjugate bioactive molecules such as drugs, ligands and imaging agents. Dendrimer prodrugs can be used to improve the water solubility and pharmacokinetic properties of the corresponding free drugs. This article summarizes preclinical studies pertaining to the use of drug-dendrimer conjugates as dendrimer prodrugs for the treatments of various diseases, including cancer and inflammatory diseases. A wide range of anticancer drugs have been conjugated to dendrimers via biodegradable linkers. The side effects of the parent drugs can be markedly reduced using dendrimer prodrugs, with some drugs showing improved efficacy. Anti-inflammatory agents have also been conjugated to dendrimers and used to treat a number of inflammatory diseases. Drug-dendrimer conjugates are preferable to drug-dendrimer complexes, where the use of degradable linkers is critical to the release of the drug. Polyethylene glycol and/or ligands can be added to a dendrimer prodrug, which is useful for the targeting of affected tissues. Imaging probes can also be incorporated into dendrimer prodrugs for the simultaneous delivery of therapeutic and diagnostic agents as 'theranostics.'

  11. Prodrugs for the Treatment of Neglected Diseases

    Directory of Open Access Journals (Sweden)

    Lorena Blau

    2007-03-01

    Full Text Available Recently, World Health Organization (WHO and Medicins San Frontieres (MSF proposed a classification of diseases as global, neglected and extremely neglected. Global diseases, such as cancer, cardiovascular and mental (CNS diseases represent the targets of the majority of the R&D efforts of pharmaceutical companies. Neglected diseases affect millions of people in the world yet existing drug therapy is limited and often inappropriate. Furthermore, extremely neglected diseases affect people living under miserable conditions who barely have access to the bare necessities for survival. Most of these diseases are excluded from the goals of the R&D programs in the pharmaceutical industry and therefore fall outside the pharmaceutical market. About 14 million people, mainly in developing countries, die each year from infectious diseases. From 1975 to 1999, 1393 new drugs were approved yet only 1% were for the treatment of neglected diseases [3]. These numbers have not changed until now, so in those countries there is an urgent need for the design and synthesis of new drugs and in this area the prodrug approach is a very interesting field. It provides, among other effects, activity improvements and toxicity decreases for current and new drugs, improving market availability. It is worth noting that it is essential in drug design to save time and money, and prodrug approaches can be considered of high interest in this respect. The present review covers 20 years of research on the design of prodrugs for the treatment of neglected and extremely neglected diseases such as Chagas’ disease (American trypanosomiasis, sleeping sickness (African trypanosomiasis, malaria, sickle cell disease, tuberculosis, leishmaniasis and schistosomiasis.

  12. Recent advances in macromolecular prodrugs

    DEFF Research Database (Denmark)

    Riber, Camilla Frich; Zelikin, Alexander N.

    2017-01-01

    Macromolecular prodrugs (MP) are high molar mass conjugates, typically carrying several copies of a drug or a drug combination, designed to optimize delivery of the drug, that is — its pharmacokinetics. From its advent several decades ago, design of MP has undergone significant development and es...

  13. A review of numerical techniques approaching microstructures of crystalline rocks

    Science.gov (United States)

    Zhang, Yahui; Wong, Louis Ngai Yuen

    2018-06-01

    The macro-mechanical behavior of crystalline rocks including strength, deformability and failure pattern are dominantly influenced by their grain-scale structures. Numerical technique is commonly used to assist understanding the complicated mechanisms from a microscopic perspective. Each numerical method has its respective strengths and limitations. This review paper elucidates how numerical techniques take geometrical aspects of the grain into consideration. Four categories of numerical methods are examined: particle-based methods, block-based methods, grain-based methods, and node-based methods. Focusing on the grain-scale characters, specific relevant issues including increasing complexity of micro-structure, deformation and breakage of model elements, fracturing and fragmentation process are described in more detail. Therefore, the intrinsic capabilities and limitations of different numerical approaches in terms of accounting for the micro-mechanics of crystalline rocks and their phenomenal mechanical behavior are explicitly presented.

  14. Prodrug strategy for cancer cell-specific targeting: A recent overview.

    Science.gov (United States)

    Zhang, Xian; Li, Xiang; You, Qidong; Zhang, Xiaojin

    2017-10-20

    The increasing development of targeted cancer therapy provides extensive possibilities in clinical trials, and numerous strategies have been explored. The prodrug is one of the most promising strategies in targeted cancer therapy to improve the selectivity and efficacy of cytotoxic compounds. Compared with normal tissues, cancer cells are characterized by unique aberrant markers, thus inactive prodrugs targeting these markers are excellent therapeutics to release active drugs, killing cancer cells without damaging normal tissues. In this review, we explore an integrated view of potential prodrugs applied in targeted cancer therapy based on aberrant cancer specific markers and some examples are provided for inspiring new ideas of prodrug strategy for cancer cell-specific targeting. Copyright © 2017. Published by Elsevier Masson SAS.

  15. Urban pavement surface temperature. Comparison of numerical and statistical approach

    Science.gov (United States)

    Marchetti, Mario; Khalifa, Abderrahmen; Bues, Michel; Bouilloud, Ludovic; Martin, Eric; Chancibaut, Katia

    2015-04-01

    The forecast of pavement surface temperature is very specific in the context of urban winter maintenance. to manage snow plowing and salting of roads. Such forecast mainly relies on numerical models based on a description of the energy balance between the atmosphere, the buildings and the pavement, with a canyon configuration. Nevertheless, there is a specific need in the physical description and the numerical implementation of the traffic in the energy flux balance. This traffic was originally considered as a constant. Many changes were performed in a numerical model to describe as accurately as possible the traffic effects on this urban energy balance, such as tires friction, pavement-air exchange coefficient, and infrared flux neat balance. Some experiments based on infrared thermography and radiometry were then conducted to quantify the effect fo traffic on urban pavement surface. Based on meteorological data, corresponding pavement temperature forecast were calculated and were compared with fiels measurements. Results indicated a good agreement between the forecast from the numerical model based on this energy balance approach. A complementary forecast approach based on principal component analysis (PCA) and partial least-square regression (PLS) was also developed, with data from thermal mapping usng infrared radiometry. The forecast of pavement surface temperature with air temperature was obtained in the specific case of urban configurtation, and considering traffic into measurements used for the statistical analysis. A comparison between results from the numerical model based on energy balance, and PCA/PLS was then conducted, indicating the advantages and limits of each approach.

  16. Numerical consistency check between two approaches to radiative ...

    Indian Academy of Sciences (India)

    approaches for a consistency check on numerical accuracy, and find out the stabil- ... ln(MR/1 GeV) to top-quark mass scale t0(= ln(mt/1 GeV)) where t0 ≤ t ≤ tR, we ..... It is in general to tone down the solar mixing angle through further fine.

  17. Some numerical approaches of creep, thermal shock, damage

    Indian Academy of Sciences (India)

    Creep can be satisfactorily described by a kinematic hardening, and exhibits different creep rates in tension and compression. Concerning the thermal shock of materials, the numerical approach depends whether or not the material is able to develop a sprayed out damage, leading to micro- or macro-cracking. Finally ...

  18. A modular approach to numerical human body modeling

    NARCIS (Netherlands)

    Forbes, P.A.; Griotto, G.; Rooij, L. van

    2007-01-01

    The choice of a human body model for a simulated automotive impact scenario must take into account both accurate model response and computational efficiency as key factors. This study presents a "modular numerical human body modeling" approach which allows the creation of a customized human body

  19. Evaluation of diclofenac prodrugs for enhancing transdermal delivery.

    Science.gov (United States)

    Lobo, Shabbir; Li, Henan; Farhan, Nashid; Yan, Guang

    2014-03-01

    Abstract Objective: The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery. Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD) and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates and bioconversion rates. In vitro fluxes across human epidermal membrane (HEM) in the Franz diffusion cell were determined on DA-, MD-, ED-, GD- and PD-saturated aqueous solutions. The formation of GD and ED led to the prodrugs with higher aqueous solubilities and lower partition coefficients than those of the parent drug. Prodrugs with improved aqueous solubility showed better fluxes across HEM in aqueous solution than that of the parent drug, with GD showing the highest aqueous solubility and also the highest flux. There is a linear relationship between the aqueous solubility and flux for DA, ED and PD, but GD and MD deviated from the linear line. Diclofenac prodrugs with improved hydrophilicity than the parent drug could be utilized for enhancing transdermal diclofenac delivery.

  20. Evaluation of Diclofenac Prodrugs for Enhancing Transdermal Delivery

    Science.gov (United States)

    Lobo, Shabbir; Li, Henan; Farhan, Nashid; Yan, Guang

    2016-01-01

    The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery. Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD), and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates, and bioconversion rates. In vitro fluxes across human epidermal membrane (HEM) in Franz diffusion cell were determined on DA, MD, ED, GD, and PD saturated aqueous solutions. The formation of GD and ED led to the prodrugs with higher aqueous solubilities and lower partition coefficients than those of the parent drug. Prodrugs with improved aqueous solubility showed better fluxes across HEM in aqueous solution than that of the parent drug, with GD showing the highest aqueous solubility and also the highest flux. There is a linear relationship between the aqueous solubility and flux for DA, ED and PD, but GD and MD deviated from the linear line. Overall, diclofenac prodrugs with improved hydrophilicity than the parent drug could be utilized for enhancing transdermal diclofenac delivery. PMID:24517636

  1. Identification of novel nitroreductases from Bacillus cereus and their interaction with the CB1954 prodrug.

    Science.gov (United States)

    Gwenin, Vanessa V; Poornima, Paramasivan; Halliwell, Jennifer; Ball, Patrick; Robinson, George; Gwenin, Chris D

    2015-12-01

    Directed enzyme prodrug therapy is a form of cancer chemotherapy in which bacterial prodrug-activating enzymes, or their encoding genes, are directed to the tumour before administration of a prodrug. The prodrug can then be activated into a toxic drug at the tumour site, reducing off-target effects. The bacterial nitroreductases are a class of enzymes used in this therapeutic approach and although very promising, the low turnover rate of prodrug by the most studied nitroreductase enzyme, NfnB from Escherichia coli (NfnB_Ec), is a major limit to this technology. There is a continual search for enzymes with greater efficiency, and as part of the search for more efficient bacterial nitroreductase enzymes, two novel enzymes from Bacillus cereus (strain ATCC 14579) have been identified and shown to reduce the CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) prodrug to its respective 2'-and 4'-hydroxylamine products. Both enzymes shared features characteristic of the nitro-FMN-reductase superfamily including non-covalently associated FMN, requirement for the NAD(P)H cofactor, homodimeric, could be inhibited by Dicoumarol (3,3'-methylenebis(4-hydroxy-2H-chromen-2-one)), and displayed ping pong bi bi kinetics. Based on the biochemical characteristics and nucleotide alignment with other nitroreductase enzymes, one enzyme was named YdgI_Bc and the other YfkO_Bc. Both B. cereus enzymes had greater turnover for the CB1954 prodrug compared with NfnB_Ec, and in the presence of added NADPH cofactor, YfkO_Bc had superior cell killing ability, and produced mainly the 4'-hydroxylamine product at low prodrug concentration. The YfkO_Bc was identified as a promising candidate for future enzyme prodrug therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Review of Methods and Approaches for Deriving Numeric ...

    Science.gov (United States)

    EPA will propose numeric criteria for nitrogen/phosphorus pollution to protect estuaries, coastal areas and South Florida inland flowing waters that have been designated Class I, II and III , as well as downstream protective values (DPVs) to protect estuarine and marine waters. In accordance with the formal determination and pursuant to a subsequent consent decree, these numeric criteria are being developed to translate and implement Florida’s existing narrative nutrient criterion, to protect the designated use that Florida has previously set for these waters, at Rule 62-302.530(47)(b), F.A.C. which provides that “In no case shall nutrient concentrations of a body of water be altered so as to cause an imbalance in natural populations of aquatic flora or fauna.” Under the Clean Water Act and EPA’s implementing regulations, these numeric criteria must be based on sound scientific rationale and reflect the best available scientific knowledge. EPA has previously published a series of peer reviewed technical guidance documents to develop numeric criteria to address nitrogen/phosphorus pollution in different water body types. EPA recognizes that available and reliable data sources for use in numeric criteria development vary across estuarine and coastal waters in Florida and flowing waters in South Florida. In addition, scientifically defensible approaches for numeric criteria development have different requirements that must be taken into consider

  3. The Feasibility of Enzyme Targeted Activation for Amino Acid/Dipeptide Monoester Prodrugs of Floxuridine; Cathepsin D as a Potential Targeted Enzyme

    Directory of Open Access Journals (Sweden)

    Gordon L. Amidon

    2012-03-01

    Full Text Available The improvement of therapeutic efficacy for cancer agents has been a big challenge which includes the increase of tumor selectivity and the reduction of adverse effects at non-tumor sites. In order to achieve those goals, prodrug approaches have been extensively investigated. In this report, the potential activation enzymes for 5¢-amino acid/dipeptide monoester floxuridine prodrugs in pancreatic cancer cells were selected and the feasibility of enzyme specific activation of prodrugs was evaluated. All prodrugs exhibited the range of 3.0–105.7 min of half life in Capan-2 cell homogenate with the presence and the absence of selective enzyme inhibitors. 5¢-O-L-Phenylalanyl-L-tyrosyl-floxuridine exhibited longer half life only with the presence of pepstatin A. Human cathepsin B and D selectively hydrolized 5¢-O-L-phenylalanyl-L-tyrosylfloxuridine and 5¢-O-L-phenylalanyl-L-glycylfloxuridine compared to the other tested prodrugs. The wide range of growth inhibitory effect by floxuridine prodrugs in Capan-2 cells was observed due to the different affinities of prodrug promoieties to enyzmes. In conclusion, it is feasible to design prodrugs which are activated by specific enzymes. Cathepsin D might be a good candidate as a target enzyme for prodrug activation and 5¢-O-L-phenylalanyl-L-tyrosylfloxuridine may be the best candidate among the tested floxuridine prodrugs.

  4. The feasibility of enzyme targeted activation for amino acid/dipeptide monoester prodrugs of floxuridine; cathepsin D as a potential targeted enzyme.

    Science.gov (United States)

    Tsume, Yasuhiro; Amidon, Gordon L

    2012-03-26

    The improvement of therapeutic efficacy for cancer agents has been a big challenge which includes the increase of tumor selectivity and the reduction of adverse effects at non-tumor sites. In order to achieve those goals, prodrug approaches have been extensively investigated. In this report, the potential activation enzymes for 5'-amino acid/dipeptide monoester floxuridine prodrugs in pancreatic cancer cells were selected and the feasibility of enzyme specific activation of prodrugs was evaluated. All prodrugs exhibited the range of 3.0-105.7 min of half life in Capan-2 cell homogenate with the presence and the absence of selective enzyme inhibitors. 5'-O-L-Phenylalanyl-L-tyrosyl-floxuridine exhibited longer half life only with the presence of pepstatin A. Human cathepsin B and D selectively hydrolized 5'-O-L-phenylalanyl-L-tyrosylfloxuridine and 5'-O-L-phenylalanyl-L-glycylfloxuridine compared to the other tested prodrugs. The wide range of growth inhibitory effect by floxuridine prodrugs in Capan-2 cells was observed due to the different affinities of prodrug promoieties to enzymes. In conclusion, it is feasible to design prodrugs which are activated by specific enzymes. Cathepsin D might be a good candidate as a target enzyme for prodrug activation and 5'-O-L-phenylalanyl-L-tyrosylfloxuridine may be the best candidate among the tested floxuridine prodrugs.

  5. Stable Numerical Approach for Fractional Delay Differential Equations

    Science.gov (United States)

    Singh, Harendra; Pandey, Rajesh K.; Baleanu, D.

    2017-12-01

    In this paper, we present a new stable numerical approach based on the operational matrix of integration of Jacobi polynomials for solving fractional delay differential equations (FDDEs). The operational matrix approach converts the FDDE into a system of linear equations, and hence the numerical solution is obtained by solving the linear system. The error analysis of the proposed method is also established. Further, a comparative study of the approximate solutions is provided for the test examples of the FDDE by varying the values of the parameters in the Jacobi polynomials. As in special case, the Jacobi polynomials reduce to the well-known polynomials such as (1) Legendre polynomial, (2) Chebyshev polynomial of second kind, (3) Chebyshev polynomial of third and (4) Chebyshev polynomial of fourth kind respectively. Maximum absolute error and root mean square error are calculated for the illustrated examples and presented in form of tables for the comparison purpose. Numerical stability of the presented method with respect to all four kind of polynomials are discussed. Further, the obtained numerical results are compared with some known methods from the literature and it is observed that obtained results from the proposed method is better than these methods.

  6. Transversal magnetotransport in Weyl semimetals: Exact numerical approach

    Science.gov (United States)

    Behrends, Jan; Kunst, Flore K.; Sbierski, Björn

    2018-02-01

    Magnetotransport experiments on Weyl semimetals are essential for investigating the intriguing topological and low-energy properties of Weyl nodes. If the transport direction is perpendicular to the applied magnetic field, experiments have shown a large positive magnetoresistance. In this work we present a theoretical scattering matrix approach to transversal magnetotransport in a Weyl node. Our numerical method confirms and goes beyond the existing perturbative analytical approach by treating disorder exactly. It is formulated in real space and is applicable to mesoscopic samples as well as in the bulk limit. In particular, we study the case of clean and strongly disordered samples.

  7. Evaluation of Diclofenac Prodrugs for Enhancing Transdermal Delivery

    OpenAIRE

    Lobo, Shabbir; Li, Henan; Farhan, Nashid; Yan, Guang

    2013-01-01

    The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery. Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD), and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates, and bioconversion rates. ...

  8. Numerical Optimization Design of Dynamic Quantizer via Matrix Uncertainty Approach

    Directory of Open Access Journals (Sweden)

    Kenji Sawada

    2013-01-01

    Full Text Available In networked control systems, continuous-valued signals are compressed to discrete-valued signals via quantizers and then transmitted/received through communication channels. Such quantization often degrades the control performance; a quantizer must be designed that minimizes the output difference between before and after the quantizer is inserted. In terms of the broadbandization and the robustness of the networked control systems, we consider the continuous-time quantizer design problem. In particular, this paper describes a numerical optimization method for a continuous-time dynamic quantizer considering the switching speed. Using a matrix uncertainty approach of sampled-data control, we clarify that both the temporal and spatial resolution constraints can be considered in analysis and synthesis, simultaneously. Finally, for the slow switching, we compare the proposed and the existing methods through numerical examples. From the examples, a new insight is presented for the two-step design of the existing continuous-time optimal quantizer.

  9. Numerical modeling of underground openings behavior with a viscoplastic approach

    International Nuclear Information System (INIS)

    Kleine, A.

    2007-01-01

    Nature is complex and must be approached in total modesty by engineers seeking to predict the behavior of underground openings. The engineering of industrial projects in underground situations, with high economic and social stakes (Alpine mountain crossings, nuclear waste repository), mean striving to gain better understanding of the behavioral mechanisms of the openings to be designed. This improvement necessarily involves better physical representativeness of macroscopic mechanisms and the provision of prediction tools suited to the expectations and needs of the engineers. The calculation tools developed in this work is in step with this concern for satisfying industrial needs and developing knowledge related to the rheology of geo-materials. These developments led to the proposing of a mechanical constitutive model, suited to lightly fissured rocks, comparable to continuous media, while integrating more particularly the effect of time. Thread of this study, the problematics ensued from the subject of the thesis is precisely about the rock mass delayed behavior in numerical modeling and its consequences on underground openings design. Based on physical concepts of reference, defined in several scales (macro/meso/micro), the developed constitutive model is translated in a mathematical formalism in order to be numerically implemented. Numerical applications presented as illustrations fall mainly within the framework of nuclear waste repository problems. They concern two very different configurations of underground openings: the AECL's underground canadian laboratory, excavated in the Lac du Bonnet granite, and the GMR gallery of Bure's laboratory (Meuse/Haute-Marne), dug in argillaceous rock. In this two cases, this constitutive model use highlights the gains to be obtained from allowing for delayed behavior regarding the accuracy of numerical tunnel behavior predictions in the short, medium and long terms. (author)

  10. Fabrication of Reductive-Responsive Prodrug Nanoparticles with Superior Structural Stability by Polymerization-Induced Self-Assembly and Functional Nanoscopic Platform for Drug Delivery.

    Science.gov (United States)

    Zhang, Wen-Jian; Hong, Chun-Yan; Pan, Cai-Yuan

    2016-09-12

    A highly efficient strategy, polymerization-induced self-assembly (PISA) for fabrication of the polymeric drug delivery systems in cancer chemotherapy is reported. Diblock prodrug copolymer, PEG-b-P(MEO2MA-co-CPTM) was used as the macro-RAFT agent to fabricate prodrug nanoparticles through PISA. The advantages of fabricating intelligent drug delivery system via this approach are as following: (1) Simultaneous fulfillment of polymerization, self-assembly, and drug encapsulation in one-pot at relatively high concentration (100 mg/mL); (2) Almost complete monomer conversion allows direct application of the resultant prodrug nanoparticles without further purification; (3) Robust structures of the resultant prodrug nanoparticles, because the cross-linker was used as the comonomer, resulted in core-cross-linking simultaneously with the formation of the prodrug nanoparticles; (4) The drug content in the resultant prodrug nanoparticles can be accurately modulated just via adjusting the feed molar ratio of MEO2MA/CPTM in the synthesis of PEG-b-P(MEO2MA-co-CPTM). The prodrug nanoparticles with similar diameters but various drug contents were obtained using different prodrug macro-CTA. In consideration of the long-term biological toxicity, the prodrug nanoparticles with higher drug content exhibit more excellent anticancer efficiency due to that lower dosage of them are enough for effectively killing HeLa cells.

  11. A finite difference, multipoint flux numerical approach to flow in porous media: Numerical examples

    KAUST Repository

    Osman, Hossam Omar; Salama, Amgad; Sun, Shuyu; Bao, Kai

    2012-01-01

    It is clear that none of the current available numerical schemes which may be adopted to solve transport phenomena in porous media fulfill all the required robustness conditions. That is while the finite difference methods are the simplest of all, they face several difficulties in complex geometries and anisotropic media. On the other hand, while finite element methods are well suited to complex geometries and can deal with anisotropic media, they are more involved in coding and usually require more execution time. Therefore, in this work we try to combine some features of the finite element technique, namely its ability to work with anisotropic media with the finite difference approach. We reduce the multipoint flux, mixed finite element technique through some quadrature rules to an equivalent cell-centered finite difference approximation. We show examples on using this technique to single-phase flow in anisotropic porous media.

  12. A finite difference, multipoint flux numerical approach to flow in porous media: Numerical examples

    KAUST Repository

    Osman, Hossam Omar

    2012-06-17

    It is clear that none of the current available numerical schemes which may be adopted to solve transport phenomena in porous media fulfill all the required robustness conditions. That is while the finite difference methods are the simplest of all, they face several difficulties in complex geometries and anisotropic media. On the other hand, while finite element methods are well suited to complex geometries and can deal with anisotropic media, they are more involved in coding and usually require more execution time. Therefore, in this work we try to combine some features of the finite element technique, namely its ability to work with anisotropic media with the finite difference approach. We reduce the multipoint flux, mixed finite element technique through some quadrature rules to an equivalent cell-centered finite difference approximation. We show examples on using this technique to single-phase flow in anisotropic porous media.

  13. Model prodrugs for the intestinal oligopeptide transporter

    DEFF Research Database (Denmark)

    Nielsen, C U; Andersen, R; Brodin, Birger

    2001-01-01

    The human intestinal di/tri-peptide carrier, hPepT1, has been suggested as a target for increasing intestinal transport of low permeability compounds by creating prodrugs designed for the transporter. Model ester prodrugs using the stabilized dipeptides D-Glu-Ala and D-Asp-Ala as pro...... with a pH of approximately 6.0, but still release the model drug at the intercellular and blood pH of approximately 7.4. Even though benzyl alcohol is not a low molecular weight drug molecule, these results indicate that the dipeptide prodrug principle is a promising drug delivery concept. However......, the physico-chemical properties such as electronegativity, solubility, and log P of the drug molecule may also have an influence on the potential of these kinds of prodrugs. The purpose of the present study is to investigate whether the model drug electronegativity, estimated as Taft substitution parameter...

  14. Numerical modelling of carbonate platforms and reefs: approaches and opportunities

    Energy Technology Data Exchange (ETDEWEB)

    Dalmasso, H.; Montaggioni, L.F.; Floquet, M. [Universite de Provence, Marseille (France). Centre de Sedimentologie-Palaeontologie; Bosence, D. [Royal Holloway University of London, Egham (United Kingdom). Dept. of Geology

    2001-07-01

    This paper compares different computing procedures that have been utilized in simulating shallow-water carbonate platform development. Based on our geological knowledge we can usually give a rather accurate qualitative description of the mechanisms controlling geological phenomena. Further description requires the use of computer stratigraphic simulation models that allow quantitative evaluation and understanding of the complex interactions of sedimentary depositional carbonate systems. The roles of modelling include: (1) encouraging accuracy and precision in data collection and process interpretation (Watney et al., 1999); (2) providing a means to quantitatively test interpretations concerning the control of various mechanisms on producing sedimentary packages; (3) predicting or extrapolating results into areas of limited control; (4) gaining new insights regarding the interaction of parameters; (5) helping focus on future studies to resolve specific problems. This paper addresses two main questions, namely: (1) What are the advantages and disadvantages of various types of models? (2) How well do models perform? In this paper we compare and discuss the application of five numerical models: CARBONATE (Bosence and Waltham, 1990), FUZZIM (Nordlund, 1999), CARBPLAT (Bosscher, 1992), DYNACARB (Li et al., 1993), PHIL (Bowman, 1997) and SEDPAK (Kendall et al., 1991). The comparison, testing and evaluation of these models allow one to gain a better knowledge and understanding of controlling parameters of carbonate platform development, which are necessary for modelling. Evaluating numerical models, critically comparing results from models using different approaches, and pushing experimental tests to their limits, provide an effective vehicle to improve and develop new numerical models. A main feature of this paper is to closely compare the performance between two numerical models: a forward model (CARBONATE) and a fuzzy logic model (FUZZIM). These two models use common

  15. Numerical approaches to time evolution of complex quantum systems

    International Nuclear Information System (INIS)

    Fehske, Holger; Schleede, Jens; Schubert, Gerald; Wellein, Gerhard; Filinov, Vladimir S.; Bishop, Alan R.

    2009-01-01

    We examine several numerical techniques for the calculation of the dynamics of quantum systems. In particular, we single out an iterative method which is based on expanding the time evolution operator into a finite series of Chebyshev polynomials. The Chebyshev approach benefits from two advantages over the standard time-integration Crank-Nicholson scheme: speedup and efficiency. Potential competitors are semiclassical methods such as the Wigner-Moyal or quantum tomographic approaches. We outline the basic concepts of these techniques and benchmark their performance against the Chebyshev approach by monitoring the time evolution of a Gaussian wave packet in restricted one-dimensional (1D) geometries. Thereby the focus is on tunnelling processes and the motion in anharmonic potentials. Finally we apply the prominent Chebyshev technique to two highly non-trivial problems of current interest: (i) the injection of a particle in a disordered 2D graphene nanoribbon and (ii) the spatiotemporal evolution of polaron states in finite quantum systems. Here, depending on the disorder/electron-phonon coupling strength and the device dimensions, we observe transmission or localisation of the matter wave.

  16. [New approaches in pharmacology: numerical modelling and simulation].

    Science.gov (United States)

    Boissel, Jean-Pierre; Cucherat, Michel; Nony, Patrice; Dronne, Marie-Aimée; Kassaï, Behrouz; Chabaud, Sylvie

    2005-01-01

    The complexity of pathophysiological mechanisms is beyond the capabilities of traditional approaches. Many of the decision-making problems in public health, such as initiating mass screening, are complex. Progress in genomics and proteomics, and the resulting extraordinary increase in knowledge with regard to interactions between gene expression, the environment and behaviour, the customisation of risk factors and the need to combine therapies that individually have minimal though well documented efficacy, has led doctors to raise new questions: how to optimise choice and the application of therapeutic strategies at the individual rather than the group level, while taking into account all the available evidence? This is essentially a problem of complexity with dimensions similar to the previous ones: multiple parameters with nonlinear relationships between them, varying time scales that cannot be ignored etc. Numerical modelling and simulation (in silico investigations) have the potential to meet these challenges. Such approaches are considered in drug innovation and development. They require a multidisciplinary approach, and this will involve modification of the way research in pharmacology is conducted.

  17. Improved Protease-Targeting and Biopharmaceutical Properties of Novel Prodrugs of Ganciclovir.

    Science.gov (United States)

    Sun, Kefeng; Xu, Hao; Hilfinger, John L; Lee, Kyung-Dall; Provoda, Chester J; Sabit, Hairat; Amidon, Gordon L

    2018-02-05

    The prodrug strategy has been frequently employed as a chemical approach for overcoming the disadvantages of existing parent drugs. In this report, we synthesized four monoester prodrugs of ganciclovir, an anticytomegalovirus drug, and demonstrated their potential advantages in protease-targeted activation and biopharmaceutical profiles over the parent compound. We demonstrated that these four prodrugs of ganciclovir, i.e., N-benzyloxycarbonyl-(L)-alanine-ganciclovir (CbzAlaGCV), N-benzyloxycarbonyl-(α,l)-aminobutyric acid-ganciclovir (CbzAbuGCV), N-acetyl-(l)-phenylalanine-(l)-alanine-ganciclovir (AcPheAlaGCV), and N-acetyl-(l)-phenylalanine-(α,l)-aminobutyric acid-ganciclovir (AcPheAbuGCV), are hydrolytically activated by the protease of human cytomegalovirus (hCMV), a serine protease that possesses intrinsic esterase activities. CbzAlaGCV and AcPheAlaGCV were found to be activated at a higher rate by the hCMV protease than CbzAbuGCV and AcPheAbuGCV. These ganciclovir prodrugs could potentially be targeted to selective activation by the hCMV protease which is only present at the viral infection sites, thereby achieving higher efficacy and lower systemic toxicity. The tissue stability, cellular uptake, and trans-epithelial transport of these ganciclovir prodrugs were also characterized. The N-acetylated dipeptide prodrugs of ganciclovir were found to be generally more stable than Cbz-amino acid prodrugs in various tissue matrices. Among the four prodrug candidates, AcPheAbuGCV was the most stable in human cell homogenates, plasma, and pooled liver microsomes. AcPheAbuGCV also possessed a superior cellular uptake profile and permeability across epithelial cell monolayers. Since the targeting and selective activation of a prodrug is determined by not only its rate of hydrolysis catalyzed by the hCMV protease target but also its biopharmaceutical properties, i.e., oral absorption and systemic availability, AcPheAbuGCV is considered the best overall candidate among

  18. Poly(ethylene glycol-Prodrug Conjugates: Concept, Design, and Applications

    Directory of Open Access Journals (Sweden)

    Shashwat S. Banerjee

    2012-01-01

    Full Text Available Poly(ethylene glycol (PEG is the most widely used polymer in delivering anticancer drugs clinically. PEGylation (i.e., the covalent attachment of PEG of peptides proteins, drugs, and bioactives is known to enhance the aqueous solubility of hydrophobic drugs, prolong circulation time, minimize nonspecific uptake, and achieve specific tumor targetability through the enhanced permeability and retention effect. Numerous PEG-based therapeutics have been developed, and several have received market approval. A vast amount of clinical experience has been gained which has helped to design PEG prodrug conjugates with improved therapeutic efficacy and reduced systemic toxicity. However, more efforts in designing PEG-based prodrug conjugates are anticipated. In light of this, the current paper highlights the synthetic advances in PEG prodrug conjugation methodologies with varied bioactive components of clinical relevance. In addition, this paper discusses FDA-approved PEGylated delivery systems, their intended clinical applications, and formulations under clinical trials.

  19. Numerical approaches to complex quantum, semiclassical and classical systems

    Energy Technology Data Exchange (ETDEWEB)

    Schubert, Gerald

    2008-11-03

    In this work we analyse the capabilities of several numerical techniques for the description of different physical systems. Thereby, the considered systems range from quantum over semiclassical to classical and from few- to many-particle systems. In chapter 1 we investigate the behaviour of a single quantum particle in the presence of an external disordered background (static potentials). Starting from the quantum percolation problem, we address the fundamental question of a disorder induced (Anderson-) transition from extended to localised single-particle eigenstates. Distinguishing isolating from conducting states by applying a local distribution approach for the local density of states (LDOS), we detect the quantum percolation threshold in two- and three-dimensions. Extending the quantum percolation model to a quantum random resistor model, we comment on the possible relevance of our results to the influence of disorder on the conductivity in graphene sheets. For the calculation of the LDOS as well as for the Chebyshev expansion of the time evolution operator, the kernel polynomial method (KPM) is the key numerical technique. In chapter 2 we examine how a single quantum particle is influenced by retarded bosonic fields that are inherent to the system. Within the Holstein model, these bosonic degrees of freedom (phonons) give rise to an infinite dimensional Hilbert space, posing a true many-particle problem. Constituting a minimal model for polaron formation, the Holstein model allows us to study the optical absorption and activated transport in polaronic systems. Using a two-dimensional variant of the KPM, we calculate for the first time quasi-exactly the optical absorption and dc-conductivity as a function of temperature. In chapter 3 we come back to the time evolution of a quantum particle in an external, static potential and investigate the capability of semiclassical approximations to it. We address basic quantum effects as tunneling, interference and

  20. Numerical approaches to complex quantum, semiclassical and classical systems

    International Nuclear Information System (INIS)

    Schubert, Gerald

    2008-01-01

    In this work we analyse the capabilities of several numerical techniques for the description of different physical systems. Thereby, the considered systems range from quantum over semiclassical to classical and from few- to many-particle systems. In chapter 1 we investigate the behaviour of a single quantum particle in the presence of an external disordered background (static potentials). Starting from the quantum percolation problem, we address the fundamental question of a disorder induced (Anderson-) transition from extended to localised single-particle eigenstates. Distinguishing isolating from conducting states by applying a local distribution approach for the local density of states (LDOS), we detect the quantum percolation threshold in two- and three-dimensions. Extending the quantum percolation model to a quantum random resistor model, we comment on the possible relevance of our results to the influence of disorder on the conductivity in graphene sheets. For the calculation of the LDOS as well as for the Chebyshev expansion of the time evolution operator, the kernel polynomial method (KPM) is the key numerical technique. In chapter 2 we examine how a single quantum particle is influenced by retarded bosonic fields that are inherent to the system. Within the Holstein model, these bosonic degrees of freedom (phonons) give rise to an infinite dimensional Hilbert space, posing a true many-particle problem. Constituting a minimal model for polaron formation, the Holstein model allows us to study the optical absorption and activated transport in polaronic systems. Using a two-dimensional variant of the KPM, we calculate for the first time quasi-exactly the optical absorption and dc-conductivity as a function of temperature. In chapter 3 we come back to the time evolution of a quantum particle in an external, static potential and investigate the capability of semiclassical approximations to it. We address basic quantum effects as tunneling, interference and

  1. Hypoxia-targeting antitumor prodrugs and photosensitizers

    International Nuclear Information System (INIS)

    Zhang Zhouen; Nishimoto, S.I.

    2006-01-01

    Tumor hypoxia has been identified as a key subject for tumor therapy, since hypoxic tumor cells show resistance to treatment of tumor tissues by radiotherapy, chemotherapy and phototherapy. For improvement of tumor radiotherapy, we have proposed a series of radiation-activated prodrugs that could selectively release antitumor agent 5-fluorouracil or 5-fluorodeoxyuridine under hypoxic conditions. Recently, we attempted to develop two families of novel hypoxia-targeting antitumor agents, considering that tumor-hypoxic environment is favorable to biological and photochemical reductions. The first family of prodrugs was derived from camptothecin as a potent topoisomerase I inhibitor and several bioreductive motifs. These prodrugs could be activated by NADPH-cytochrome P450 reductase or DT-diaphorase to release free camptothecin, and thereby showed hypoxia-selective cytotoxictiy towards tumor cells. These prodrugs were also applicable to the real-time monitoring of activation and antitumor effect by fluorometry. Furthermore, the camptothecin-bioreductive motif conjugates was confirmed to show an oxygen-independent DAN photocleaving activity, which could overcome a drawback of back electron transfer occurring in the photosensitized one-electron oxidation of DNA. Thus, these camptothecin derivatives could be useful to both chemotherapy and phototherapy for hypoxic tumor cells. The second family of prodrugs harnessed UV light for cancer therapy, incorporating the antitumor agent 5-fluorourcil and the photolabile 2-nitrobenzyl chromophores. The attachment of a tumor-homing cyclic peptide CNGRC was also employed to construct the prototype of tumor-targeting photoactiaved antitumor prodrug. These novel prodrugs released high yield of 5-fluorourcil upon UV irradiation at λ ex =365 nm, while being quite stable in the dark. The photoactivation mechanism was also clarified by means of nanosecond laser flash photolysis. (authors)

  2. Numerical modelling of diesel spray using the Eulerian multiphase approach

    International Nuclear Information System (INIS)

    Vujanović, Milan; Petranović, Zvonimir; Edelbauer, Wilfried; Baleta, Jakov; Duić, Neven

    2015-01-01

    Highlights: • Numerical model for fuel disintegration was presented. • Fuel liquid and vapour were calculated. • Good agreement with experimental data was shown for various combinations of injection and chamber pressure. - Abstract: This research investigates high pressure diesel fuel injection into the combustion chamber by performing computational simulations using the Euler–Eulerian multiphase approach. Six diesel-like conditions were simulated for which the liquid fuel jet was injected into a pressurised inert environment (100% N 2 ) through a 205 μm nozzle hole. The analysis was focused on the liquid jet and vapour penetration, describing spatial and temporal spray evolution. For this purpose, an Eulerian multiphase model was implemented, variations of the sub-model coefficients were performed, and their impact on the spray formation was investigated. The final set of sub-model coefficients was applied to all operating points. Several simulations of high pressure diesel injections (50, 80, and 120 MPa) combined with different chamber pressures (5.4 and 7.2 MPa) were carried out and results were compared to the experimental data. The predicted results share a similar spray cloud shape for all conditions with the different vapour and liquid penetration length. The liquid penetration is shortened with the increase in chamber pressure, whilst the vapour penetration is more pronounced by elevating the injection pressure. Finally, the results showed good agreement when compared to the measured data, and yielded the correct trends for both the liquid and vapour penetrations under different operating conditions

  3. Unsteady flow phenomena in human undulatory swimming: a numerical approach.

    Science.gov (United States)

    Pacholak, Steffen; Hochstein, Stefan; Rudert, Alexander; Brücker, Christoph

    2014-06-01

    The undulatory underwater sequence is one of the most important phases in competitive swimming. An understanding of the recurrent vortex dynamics around the human body and their generation could therefore be used to improve swimming techniques. In order to produce a dynamic model, we applied human joint kinematics to three-dimensional (3D) body scans of a female swimmer. The flow around this dynamic model was then calculated using computational fluid dynamics with the aid of moving 3D meshes. Evaluation of the numerical results delivered by the various motion cycles identified characteristic vortex structures for each of the cycles, which exhibited increasing intensity and drag influence. At maximum thrust, drag forces appear to be 12 times higher than those of a passive gliding swimmer. As far as we know, this is the first disclosure of vortex rings merging into vortex tubes in the wake after vortex recapturing. All unsteady structures were visualized using a modified Q-criterion also incorporated into our methods. At the very least, our approach is likely to be suited to further studies examining swimmers engaging in undulatory swimming during training or competition.

  4. Numerical approaches to model perturbation fire in turing pattern formations

    Science.gov (United States)

    Campagna, R.; Brancaccio, M.; Cuomo, S.; Mazzoleni, S.; Russo, L.; Siettos, K.; Giannino, F.

    2017-11-01

    Turing patterns were observed in chemical, physical and biological systems described by coupled reaction-diffusion equations. Several models have been formulated proposing the water as the causal mechanism of vegetation pattern formation, but this isn't an exhaustive hypothesis in some natural environments. An alternative explanation has been related to the plant-soil negative feedback. In Marasco et al. [1] the authors explored the hypothesis that both mechanisms contribute in the formation of regular and irregular vegetation patterns. The mathematical model consists in three partial differential equations (PDEs) that take into account for a dynamic balance between biomass, water and toxic compounds. A numerical approach is mandatory also to investigate on the predictions of this kind of models. In this paper we start from the mathematical model described in [1], set the model parameters such that the biomass reaches a stable spatial pattern (spots) and present preliminary studies about the occurrence of perturbing events, such as wildfire, that can affect the regularity of the biomass configuration.

  5. Photoactivatable Caged Prodrugs of VEGFR-2 Kinase Inhibitors

    OpenAIRE

    Boris Pinchuk; Rebecca Horbert; Alexander Döbber; Lydia Kuhl; Christian Peifer

    2016-01-01

    In this study, we report on the design, synthesis, photokinetic properties and in vitro evaluation of photoactivatable caged prodrugs for the receptor tyrosine kinase VEGFR-2. Highly potent VEGFR-2 inhibitors 1 and 3 were caged by introduction of a photoremovable protecting group (PPG) to yield the caged prodrugs 4 and 5. As expected, enzymatic and cellular proliferation assays showed dramatically diminished efficacy of caged prodrugs in vitro. Upon ultraviolet (UV) irradiation of the prodrug...

  6. Prodrugs of herpes simplex thymidine kinase inhibitors.

    Science.gov (United States)

    Yanachkova, Milka; Xu, Wei-Chu; Dvoskin, Sofya; Dix, Edward J; Yanachkov, Ivan B; Focher, Federico; Savi, Lida; Sanchez, M Dulfary; Foster, Timothy P; Wright, George E

    2015-04-01

    Because guanine-based herpes simplex virus thymidine kinase inhibitors are not orally available, we synthesized various 6-deoxy prodrugs of these compounds and evaluated them with regard to solubility in water, oral bioavailability, and efficacy to prevent herpes simplex virus-1 reactivation from latency in a mouse model. Organic synthesis was used to prepare compounds, High Performance Liquid Chromatography (HPLC) to analyze hydrolytic conversion, Mass Spectrometry (MS) to measure oral bioavailability, and mouse latent infection and induced reactivation to evaluate the efficacy of a specific prodrug. Aqueous solubilities of prodrugs were improved, oxidation of prodrugs by animal cytosols occurred in vitro, and oral absorption of the optimal prodrug sacrovir™ (6-deoxy-mCF3PG) in the presence of the aqueous adjuvant Soluplus® and conversion to active compound N(2)-[3-(trifluoromethyl)pheny])guanine (mCF3PG) were accomplished in mice. Treatment of herpes simplex virus-1 latent mice with sacrovir™ in 1% Soluplus in drinking water significantly suppressed herpes simplex virus-1 reactivation and viral genomic replication. Ad libitum oral delivery of sacrovir™ was effective in suppressing herpes simplex virus-1 reactivation in ocularly infected latent mice as measured by the numbers of mice shedding infectious virus at the ocular surface, numbers of trigeminal ganglia positive for infectious virus, number of corneas that had detectable infectious virus, and herpes simplex virus-1 genome copy numbers in trigeminal ganglia following reactivation. These results demonstrate the statistically significant effect of the prodrug on suppressing herpes simplex virus-1 reactivation in vivo. © The Author(s) 2015.

  7. [In vitro metabolism of fenbendazole prodrug].

    Science.gov (United States)

    Wen, Ai-Dan; Duan, Li-Ping; Liu, Cong-Shan; Tao, Yi; Xue, Jian; Wu, Ning-Bo; Jiang, Bin; Zhang, Hao-Bing

    2013-02-01

    Synthesized fenbendazole prodrug N-methoxycarbonyl-N'-(2-nitro-4-phenylthiophenyl) thiourea (MPT) was analyzed in vitro in artificial gastric juice, intestinal juice and mouse liver homogenate model by using HPLC method, and metabolic curve was then generated. MPT was tested against Echinococcus granulosus protoscolices in vitro. The result showed that MPT could be metabolized in the three biological media, and to the active compound fenbendazole in liver homogenate, with a metabolic rate of 7.92%. Besides, the prodrug showed a weak activity against E. granulosus protoscolices with a mortality of 45.9%.

  8. Cationic polymeric gene delivery of beta-glucuronidase for doxorubicin prodrug therapy

    NARCIS (Netherlands)

    Fonseca, MJ; Storm, G; Hennink, WE; Gerritsen, WR; Haisma, HJ

    1999-01-01

    Background An approach to improve current chemotherapy is the selective transduction of tumor cells with suicide genes to sensitize these cells to prodrugs of cytostatic agents; Methods In this study, gene transfer was accomplished with the cationic polymer poly(2-(dimethylamino)ethyl methacrylate)

  9. Numerical Methods for Stochastic Computations A Spectral Method Approach

    CERN Document Server

    Xiu, Dongbin

    2010-01-01

    The first graduate-level textbook to focus on fundamental aspects of numerical methods for stochastic computations, this book describes the class of numerical methods based on generalized polynomial chaos (gPC). These fast, efficient, and accurate methods are an extension of the classical spectral methods of high-dimensional random spaces. Designed to simulate complex systems subject to random inputs, these methods are widely used in many areas of computer science and engineering. The book introduces polynomial approximation theory and probability theory; describes the basic theory of gPC meth

  10. An Energy Based Numerical Approach to Phase Change Problems

    DEFF Research Database (Denmark)

    Hauggaard-Nielsen, Anders Boe; Damkilde, Lars; Krenk, Steen

    1996-01-01

    Phase change problems, occurring e.g. in melting, casting and freezing processes, are often characterized by a very narrow transition zone with very lareg changes in heat capacity and conductivity. This leads to problems in numerical procedures, where the transition zone propagates through a mesh...

  11. Two Numerical Approaches to Stationary Mean-Field Games

    KAUST Repository

    Almulla, Noha; Ferreira, Rita; Gomes, Diogo A.

    2016-01-01

    Here, we consider numerical methods for stationary mean-field games (MFG) and investigate two classes of algorithms. The first one is a gradient-flow method based on the variational characterization of certain MFG. The second one uses monotonicity properties of MFG. We illustrate our methods with various examples, including one-dimensional periodic MFG, congestion problems, and higher-dimensional models.

  12. Numerical approaches towards life cycle interpretation five examples

    NARCIS (Netherlands)

    Heijungs, R.; Kleijn, R.

    2001-01-01

    The ISO-standard for LCA distinguishes four phases, of which the last one, the interpretation, is the least elaborated. It can be regarded as containing procedural steps (like a completeness check) as well as numerical steps (like a sensitivity check). This paper provides five examples of techniques

  13. Two Numerical Approaches to Stationary Mean-Field Games

    KAUST Repository

    Almulla, Noha

    2016-10-04

    Here, we consider numerical methods for stationary mean-field games (MFG) and investigate two classes of algorithms. The first one is a gradient-flow method based on the variational characterization of certain MFG. The second one uses monotonicity properties of MFG. We illustrate our methods with various examples, including one-dimensional periodic MFG, congestion problems, and higher-dimensional models.

  14. Contribution to the damping identification: experimental and numerical approaches

    International Nuclear Information System (INIS)

    Crambuer, R.

    2013-01-01

    Since earthquakes are a natural threat in France, it seems reasonable to construct buildings capable of resisting them. Since 1955, A.S. 55 recommendations regulations have taken into account this risk in all new constructions. The rules were created following an earthquake in Orleansville (Algeria) on 9. September 1954 and since then they have been modified in the aftermath of several significant earthquakes. As it stands now, the law requires that measurements of energy dissipation be carried out during the earthquakes in an effective manner. However, at present it is a great challenge to determine this, especially where reinforced concrete structures are concerned. The reason for this is the many different causes of energy dissipation which can be material, such as steel yielding, cracking of the concrete or deterioration of the interface between the Steel/concrete interface or environmental, such as the interactions with neighbouring structures or radiative damping. These dissipations typically creep into the essential pattern of the structures as a uniform, slight damping, and which is heavily quantify such as modal or Rayleigh damping. The challenge is therefore to ascertain how to carry out damping in a way that relies more on the laws of physics themselves. This study aims at bringing some clarifications to this problem. In order to achieve this, two objectives were targeted during the case study: the first consisted in experimentally qualifying and quantifying the sources of damping in concrete, the second aims at developing a method which model both the overall behaviour and the damping in a realistic way with low computational costs. A series of reverse 3-point bending tests were carried out to determine and quantify the mechanisms responsible for damping. This approach was innovative in that the tests were carried out on not only sound beams, but also on pre-damaged beams. When processing the results of these experiments, we focused on the overall

  15. Supramolecular curcumin-barium prodrugs for formulating with ceramic particles.

    Science.gov (United States)

    Kamalasanan, Kaladhar; Anupriya; Deepa, M K; Sharma, Chandra P

    2014-10-01

    properties in the combined formulations. Our proof concept study shows that, the conversion of curcumin to a metal-organic supramolecular prodrug improved the solubility, stability and release profile of curcumin. The prodrug approach with the micellisation strategy appears to be more appropriate to deliver intact curcumin in the presence of ceramic particles of varying surface reactivity. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. A cubic B-spline Galerkin approach for the numerical simulation of the GEW equation

    Directory of Open Access Journals (Sweden)

    S. Battal Gazi Karakoç

    2016-02-01

    Full Text Available The generalized equal width (GEW wave equation is solved numerically by using lumped Galerkin approach with cubic B-spline functions. The proposed numerical scheme is tested by applying two test problems including single solitary wave and interaction of two solitary waves. In order to determine the performance of the algorithm, the error norms L2 and L∞ and the invariants I1, I2 and I3 are calculated. For the linear stability analysis of the numerical algorithm, von Neumann approach is used. As a result, the obtained findings show that the presented numerical scheme is preferable to some recent numerical methods.  

  17. Data Shuffling--A New Masking Approach for Numerical Data

    OpenAIRE

    Krishnamurty Muralidhar; Rathindra Sarathy

    2006-01-01

    This study discusses a new procedure for masking confidential numerical data--a procedure called data shuffling--in which the values of the confidential variables are "shuffled" among observations. The shuffled data provides a high level of data utility and minimizes the risk of disclosure. From a practical perspective, data shuffling overcomes reservations about using perturbed or modified confidential data because it retains all the desirable properties of perturbation methods and performs ...

  18. Numerical

    Directory of Open Access Journals (Sweden)

    M. Boumaza

    2015-07-01

    Full Text Available Transient convection heat transfer is of fundamental interest in many industrial and environmental situations, as well as in electronic devices and security of energy systems. Transient fluid flow problems are among the more difficult to analyze and yet are very often encountered in modern day technology. The main objective of this research project is to carry out a theoretical and numerical analysis of transient convective heat transfer in vertical flows, when the thermal field is due to different kinds of variation, in time and space of some boundary conditions, such as wall temperature or wall heat flux. This is achieved by the development of a mathematical model and its resolution by suitable numerical methods, as well as performing various sensitivity analyses. These objectives are achieved through a theoretical investigation of the effects of wall and fluid axial conduction, physical properties and heat capacity of the pipe wall on the transient downward mixed convection in a circular duct experiencing a sudden change in the applied heat flux on the outside surface of a central zone.

  19. Modification of concomitant drug release from oil vehicles using drug-prodrug combinations to achieve sustained balanced analgesia after joint installation

    DEFF Research Database (Denmark)

    Thing, Mette; Jensen, Sabrine Smedegaard; Larsen, Claus Selch

    2012-01-01

    Intra-articular injection of two drugs in a sustained drug delivery system combining the use of lipophilic solution with the prodrug approach may provide efficient and prolonged postoperative pain treatment after arthroscopic procedures. In the present study, the concomitant release of N...... using buffer. In both release models, the use of ropivacaine-prodrug combination provided concomitant release from the oil into synovial fluid with ropivacaine being released faster than naproxen. The use of lipophilic prodrugs that are converted fast to the parent drug in synovial fluid seems...

  20. Mechanical behaviour of the heel pad: experimental and numerical approach

    DEFF Research Database (Denmark)

    Matteoli, Sara; Fontanella, C. G.; Virga, A.

    The aim of the present work was to investigate the stress relaxation phenomena of the heel pad region under different loading conditions. A 31-year-old healthy female was enrolled in this study and her left foot underwent both MRI and experimental compression tests. Experimental results were...... compared with those obtained from finite element analysis performed on numerical 3D subject-specific heel pad model built on the basis of MRI. The calcaneal fat pad tissue was described with a visco-hyperelastic model, while a fiber-reinforced hyperelastic model was formulated for the skin. The reliability...

  1. Heat transfer enhancement in nanofluids. A numerical approach

    International Nuclear Information System (INIS)

    Fariñas Alvariño, P; Sáiz Jabardo, J M; Arce, A; Llamas Galdo, M I

    2012-01-01

    The aim of the reported investigation is to asses the effect of brownian and thermophoretic diffusion in nanofluids convective heat transfer. In order to capture these effects, a new equation for particles distribution had to be consider. Momentum and energy equations have been reformulated in order to include brownian and thermophretic diffusion. These modes of diffusion have been suggested extensively in the literature but their effect on momentum and energy transport has not yet been numerically analyzed. In order to obtain a solution for the modified set of governing equations, a new CFD solver had to be devised. The new solver has been applied to a case study involving hydrodynamic and thermally developing laminar flow regime in a pipe. Pure base fluid solutions have been used to asses the accuracy of the model. Numerical nanofluid solutions compare reasonably well with both experimental results obtained elsewhere and the Churchill and Ozoe correlation. The observed heat transfer enhancement by the nanofluid has been attributed to its transport properties rather than to another transport mechanism.

  2. Numerical Approach of Coupling Vibration Magneto-convection In Nanofluid

    Directory of Open Access Journals (Sweden)

    K Syham

    2016-06-01

    Full Text Available The objective of our work is to visualize numerically the effect of coupling vibratory excitation and magnetic field on cooling an electronic component or a solar cell (originality of our study in arid and semi-arid area. A square cavity of side H filled with Al2O3-water nanofluid where an electronic component is placed on the bottom horizontal wall is maintained at isothermal hot temperature Th. The top horizontal wall is maintained at a cold temperature Tc. The vertical walls are adiabatic. The equations describing the natural convection flow in the square cavity consist of mass conservation, momentum and energy. For the physical parameters of Al2O3-water nanofluid, we use the Brinkman and Wasp model. Transport equations are solved numerically by finite element method. The results are obtained for Rayleigh number Ra= 105, Hartmann numbers between 0 and 100 and vibratory excitation inclination angle between 0° and 90°. The external magnetic field inclination angle varies between 0° and 90° and the Rayleigh number ratio between 0 and 50.  Results are presented in the form of heat transfer flux ratio and maximum absolute value of stream function.

  3. Advanced approach to numerical forecasting using artificial neural networks

    Directory of Open Access Journals (Sweden)

    Michael Štencl

    2009-01-01

    Full Text Available Current global market is driven by many factors, such as the information age, the time and amount of information distributed by many data channels it is practically impossible analyze all kinds of incoming information flows and transform them to data with classical methods. New requirements could be met by using other methods. Once trained on patterns artificial neural networks can be used for forecasting and they are able to work with extremely big data sets in reasonable time. The patterns used for learning process are samples of past data. This paper uses Radial Basis Functions neural network in comparison with Multi Layer Perceptron network with Back-propagation learning algorithm on prediction task. The task works with simplified numerical time series and includes forty observations with prediction for next five observations. The main topic of the article is the identification of the main differences between used neural networks architectures together with numerical forecasting. Detected differences then verify on practical comparative example.

  4. Stepwise-activable multifunctional peptide-guided prodrug micelles for cancerous cells intracellular drug release

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jing, E-mail: zhangjing@zjut.edu.cn; Li, Mengfei [Zhejiang University of Technology, College of Materials Science and Engineering (China); Yuan, Zhefan [Zhejiang University, Key Laboratory of Biomass Chemical Engineering of Ministry of Education, Department of Chemical and Biological Engineering (China); Wu, Dan; Chen, Jia-da; Feng, Jie, E-mail: fengjie@zjut.edu.cn [Zhejiang University of Technology, College of Materials Science and Engineering (China)

    2016-10-15

    be activated by charge reversal of the prodrug micelles via hydrolysis of acid-labile β-carboxylic amides and regeneration of K{sub 10}. The cell-penetrating peptide, K{sub 10}, would enable efficient internalization of MPPM by tumor cells, and the drug would be rapidly released induced by concentrated glutathione and numerous proteases inside the cancerous cells, resulting in the inhibited effect of the cells.

  5. Complex transfers in porous media: some physical and numerical approaches

    International Nuclear Information System (INIS)

    Maugis, P.

    2006-06-01

    The feasibility and safety of nuclear waste storage containers is studied. The thermodynamics of water/air flow is described and applied, via a simplified numerical model, to a simple experimental apparatus yielding heat pipe effect. The 2D influence of deterministic boundary conditions is important on kinematics and transport. Dispersivity depends on the nonuniform flow type and integrates the often marginal Gaussian part of plume spreading. A new algorithm, based on jump locality and recalibration, avoids the small bias induced by inter-cell diffusive jumps. Several algorithms modeling transport of decaying, soluble, sorbing, or precipitating species are compared. Stability and precision criteria are analyzed. Up-stream over-precipitation and negative down-stream concentrations are observed for high solubility contrasts. (author)

  6. Numerical approach to the inverse convection-diffusion problem

    International Nuclear Information System (INIS)

    Yang, X-H; She, D-X; Li, J-Q

    2008-01-01

    In this paper, the inverse problem on source term identification in convection-diffusion equation is transformed into an optimization problem. To reduce the computational cost and improve computational accuracy for the optimization problem, a new algorithm, chaos real-coded hybrid-accelerating evolution algorithm (CRHAEA), is proposed, in which an initial population is generated by chaos mapping, and new chaos mutation and simplex evolution operation are used. With the shrinking of searching range, CRHAEA gradually directs to an optimal result with the excellent individuals obtained by real-coded evolution algorithm. Its convergence is analyzed. Its efficiency is demonstrated by 15 test functions. Numerical simulation shows that CRHAEA has some advantages over the real-coded accelerated evolution algorithm, the chaos algorithm and the pure random search algorithm

  7. Asynchronous machine rotor speed estimation using a tabulated numerical approach

    Science.gov (United States)

    Nguyen, Huu Phuc; De Miras, Jérôme; Charara, Ali; Eltabach, Mario; Bonnet, Stéphane

    2017-12-01

    This paper proposes a new method to estimate the rotor speed of the asynchronous machine by looking at the estimation problem as a nonlinear optimal control problem. The behavior of the nonlinear plant model is approximated off-line as a prediction map using a numerical one-step time discretization obtained from simulations. At each time-step, the speed of the induction machine is selected satisfying the dynamic fitting problem between the plant output and the predicted output, leading the system to adopt its dynamical behavior. Thanks to the limitation of the prediction horizon to a single time-step, the execution time of the algorithm can be completely bounded. It can thus easily be implemented and embedded into a real-time system to observe the speed of the real induction motor. Simulation results show the performance and robustness of the proposed estimator.

  8. Numerical Simulation of Incremental Sheet Forming by Simplified Approach

    Science.gov (United States)

    Delamézière, A.; Yu, Y.; Robert, C.; Ayed, L. Ben; Nouari, M.; Batoz, J. L.

    2011-01-01

    The Incremental Sheet Forming (ISF) is a process, which can transform a flat metal sheet in a 3D complex part using a hemispherical tool. The final geometry of the product is obtained by the relative movement between this tool and the blank. The main advantage of that process is that the cost of the tool is very low compared to deep drawing with rigid tools. The main disadvantage is the very low velocity of the tool and thus the large amount of time to form the part. Classical contact algorithms give good agreement with experimental results, but are time consuming. A Simplified Approach for the contact management between the tool and the blank in ISF is presented here. The general principle of this approach is to imposed displacement of the nodes in contact with the tool at a given position. On a benchmark part, the CPU time of the present Simplified Approach is significantly reduced compared with a classical simulation performed with Abaqus implicit.

  9. An efficient numerical approach to electrostatic microelectromechanical system simulation

    International Nuclear Information System (INIS)

    Pu, Li

    2009-01-01

    Computational analysis of electrostatic microelectromechanical systems (MEMS) requires an electrostatic analysis to compute the electrostatic forces acting on micromechanical structures and a mechanical analysis to compute the deformation of micromechanical structures. Typically, the mechanical analysis is performed on an undeformed geometry. However, the electrostatic analysis is performed on the deformed position of microstructures. In this paper, a new efficient approach to self-consistent analysis of electrostatic MEMS in the small deformation case is presented. In this approach, when the microstructures undergo small deformations, the surface charge densities on the deformed geometry can be computed without updating the geometry of the microstructures. This algorithm is based on the linear mode shapes of a microstructure as basis functions. A boundary integral equation for the electrostatic problem is expanded into a Taylor series around the undeformed configuration, and a new coupled-field equation is presented. This approach is validated by comparing its results with the results available in the literature and ANSYS solutions, and shows attractive features comparable to ANSYS. (general)

  10. A time-spectral approach to numerical weather prediction

    Science.gov (United States)

    Scheffel, Jan; Lindvall, Kristoffer; Yik, Hiu Fai

    2018-05-01

    Finite difference methods are traditionally used for modelling the time domain in numerical weather prediction (NWP). Time-spectral solution is an attractive alternative for reasons of accuracy and efficiency and because time step limitations associated with causal CFL-like criteria, typical for explicit finite difference methods, are avoided. In this work, the Lorenz 1984 chaotic equations are solved using the time-spectral algorithm GWRM (Generalized Weighted Residual Method). Comparisons of accuracy and efficiency are carried out for both explicit and implicit time-stepping algorithms. It is found that the efficiency of the GWRM compares well with these methods, in particular at high accuracy. For perturbative scenarios, the GWRM was found to be as much as four times faster than the finite difference methods. A primary reason is that the GWRM time intervals typically are two orders of magnitude larger than those of the finite difference methods. The GWRM has the additional advantage to produce analytical solutions in the form of Chebyshev series expansions. The results are encouraging for pursuing further studies, including spatial dependence, of the relevance of time-spectral methods for NWP modelling.

  11. Strategy for a numerical Rock Mechanics Site Descriptive Model. Further development of the theoretical/numerical approach

    International Nuclear Information System (INIS)

    Olofsson, Isabelle; Fredriksson, Anders

    2005-05-01

    The Swedish Nuclear and Fuel Management Company (SKB) is conducting Preliminary Site Investigations at two different locations in Sweden in order to study the possibility of a Deep Repository for spent fuel. In the frame of these Site Investigations, Site Descriptive Models are achieved. These products are the result of an interaction of several disciplines such as geology, hydrogeology, and meteorology. The Rock Mechanics Site Descriptive Model constitutes one of these models. Before the start of the Site Investigations a numerical method using Discrete Fracture Network (DFN) models and the 2D numerical software UDEC was developed. Numerical simulations were the tool chosen for applying the theoretical approach for characterising the mechanical rock mass properties. Some shortcomings were identified when developing the methodology. Their impacts on the modelling (in term of time and quality assurance of results) were estimated to be so important that the improvement of the methodology with another numerical tool was investigated. The theoretical approach is still based on DFN models but the numerical software used is 3DEC. The main assets of the programme compared to UDEC are an optimised algorithm for the generation of fractures in the model and for the assignment of mechanical fracture properties. Due to some numerical constraints the test conditions were set-up in order to simulate 2D plane strain tests. Numerical simulations were conducted on the same data set as used previously for the UDEC modelling in order to estimate and validate the results from the new methodology. A real 3D simulation was also conducted in order to assess the effect of the '2D' conditions in the 3DEC model. Based on the quality of the results it was decided to update the theoretical model and introduce the new methodology based on DFN models and 3DEC simulations for the establishment of the Rock Mechanics Site Descriptive Model. By separating the spatial variability into two parts, one

  12. Numerical simulation in steam injection process by a mechanistic approach

    Energy Technology Data Exchange (ETDEWEB)

    De Souza, J.C.Jr.; Campos, W.; Lopes, D.; Moura, L.S.S. [Petrobras, Rio de Janeiro (Brazil)

    2008-10-15

    Steam injection is a common thermal recovery method used in very viscous oil reservoirs. The method involves the injection of heat to reduce viscosity and mobilize oil. A steam generation and injection system consists primarily of a steam source, distribution lines, injection wells and a discarding tank. In order to optimize injection and improve the oil recovery factor, one must determine the parameters of steam flow such as pressure, temperature and steam quality. This study focused on developing a unified mathematical model by means of a mechanistic approach for two-phase steam flow in pipelines and wells. The hydrodynamic and heat transfer mechanistic model was implemented in a computer simulator to model the parameters of steam injection while trying to avoid the use of empirical correlations. A marching algorithm was used to determine the distribution of pressure and temperature along the pipelines and wellbores. The mathematical model for steam flow in injection systems, developed by a mechanistic approach (VapMec) performed well when the simulated values of pressures and temperatures were compared with the values measured during field tests. The newly developed VapMec model was incorporated in the LinVap-3 simulator that constitutes an engineering supporting tool for steam injection wells operated by Petrobras. 23 refs., 7 tabs., 6 figs.

  13. Pharmacokinetics of Curcumin Diethyl Disuccinate, a Prodrug of Curcumin, in Wistar Rats.

    Science.gov (United States)

    Bangphumi, Kunan; Kittiviriyakul, Chuleeporn; Towiwat, Pasarapa; Rojsitthisak, Pornchai; Khemawoot, Phisit

    2016-12-01

    Curcumin is the major bioactive component of turmeric, but has poor oral bioavailability that limits its clinical applications. To improve the in vitro solubility and alkaline stability, we developed a prodrug of curcumin by succinylation to obtain curcumin diethyl disuccinate, with the goal of improving the oral bioavailability of curcumin. The in vivo pharmacokinetic profile of curcumin diethyl disuccinate was compared with that of curcumin in male Wistar rats. Doses of curcumin 20 mg/kg intravenous or 40 mg/kg oral were used as standard regimens for comparison with the prodrug at equivalent doses in healthy adult rats. Blood, tissues, urine, and faeces were collected from time zero to 48 h after dosing to determine the prodrug level, curcumin level and a major metabolite by liquid chromatography-tandem spectrometry. The absolute oral bioavailability of curcumin diethyl disuccinate was not significantly improved compared with curcumin, with both compounds having oral bioavailability of curcumin less than 1 %. The major metabolic pathway of the prodrug was rapid hydrolysis to obtain curcumin, followed by glucuronidation. Interestingly, curcumin diethyl disuccinate gave superior tissue distribution with higher tissue to plasma ratio of curcumin and curcumin glucuronide in several organs after intravenous dosing at 1 and 4 h. The primary elimination route of curcumin glucuronide occurred via biliary and faecal excretion, with evidence of an entry into the enterohepatic circulation. Curcumin diethyl disuccinate did not significantly improve the oral bioavailability of curcumin due to first pass metabolism in the gastrointestinal tract. Further studies on reduction of first pass metabolism are required to optimise delivery of curcumin using a prodrug approach.

  14. Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling

    Directory of Open Access Journals (Sweden)

    Annika Bettina Foehrenbacher

    2013-12-01

    Full Text Available Hypoxia contributes to resistance of tumors to some cytotoxic drugs and to radiotherapy, but can in principle be exploited with hypoxia-activated prodrugs (HAP. HAP in clinical development fall into two broad groups. Class I HAP (like the benzotriazine N-oxides tirapazamine and SN30000, are activated under relatively mild hypoxia. In contrast, Class II HAP (such as the nitro compounds PR-104A or TH-302 are maximally activated only under extreme hypoxia, but their active metabolites (effectors diffuse to cells at intermediate O2 and thus also eliminate moderately hypoxic cells. Here, we use a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD model to compare these two strategies and to identify the features required in an optimal Class II HAP. The model uses a Green’s function approach to calculate spatial and longitudinal gradients of O2, prodrug and effector concentrations, and resulting killing in a digitized 3D tumor microregion to estimate activity as monotherapy and in combination with radiotherapy. An analogous model for a normal tissue with mild hypoxia and short intervesssel distances (based on a cremaster muscle microvessel network was used to estimate tumor selectivity of cell killing. This showed that Class II HAP offer advantages over Class I including higher tumor selectivity and greater freedom to vary prodrug diffusibility and rate of metabolic activation. The model suggests that the largest gains in class II HAP antitumor activity could be realized by optimizing effector stability and prodrug activation rates. We also use the model to show that diffusion of effector into blood vessels is unlikely to materially increase systemic exposure for realistic tumor burdens and effector clearances. However, we show that the tumor selectivity achievable by hypoxia-dependent prodrug activation alone is limited if dose-limiting normal tissues are even mildly hypoxic

  15. Suppression of inflammation in a mouse model of rheumatoid arthritis using targeted lipase-labile fumagillin prodrug nanoparticles.

    Science.gov (United States)

    Zhou, Hui-Fang; Yan, Huimin; Senpan, Angana; Wickline, Samuel A; Pan, Dipanjan; Lanza, Gregory M; Pham, Christine T N

    2012-11-01

    Nanoparticle-based therapeutics are emerging technologies that have the potential to greatly impact the treatment of many human diseases. However, drug instability and premature release from the nanoparticles during circulation currently preclude clinical translation. Herein, we use a lipase-labile (Sn 2) fumagillin prodrug platform coupled with a unique lipid surface-to-surface targeted delivery mechanism, termed contact-facilitated drug delivery, to counter the premature drug release and overcome the inherent photo-instability of fumagillin, an established anti-angiogenic agent. We show that α(v)β(3)-integrin targeted fumagillin prodrug nanoparticles, administered at 0.3 mg of fumagillin prodrug/kg of body weight suppress the clinical disease indices of KRN serum-mediated arthritis in a dose-dependent manner when compared to treatment with the control nanoparticles with no drug. This study demonstrates the effectiveness of this lipase-labile prodrug nanocarrier in a relevant preclinical model that approximates human rheumatoid arthritis. The lipase-labile prodrug paradigm offers a translatable approach that is broadly applicable to many targeted nanosystems and increases the translational potential of this platform for many diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Variability of orogenic magmatism during Mediterranean-style continental collisions : A numerical modelling approach

    NARCIS (Netherlands)

    Andrić, N.; Vogt, K.; Matenco, L.; Cvetković, V.; Cloetingh, S.; Gerya, T.

    The relationship between magma generation and the tectonic evolution of orogens during subduction and subsequent collision requires self-consistent numerical modelling approaches predicting volumes and compositions of the produced magmatic rocks. Here, we use a 2D magmatic-thermomechanical numerical

  17. Component-oriented approach to the development and use of numerical models in high energy physics

    International Nuclear Information System (INIS)

    Amelin, N.S.; Komogorov, M.Eh.

    2002-01-01

    We discuss the main concepts of a component approach to the development and use of numerical models in high energy physics. This approach is realized as the NiMax software system. The discussed concepts are illustrated by numerous examples of the system user session. In appendix chapter we describe physics and numerical algorithms of the model components to perform simulation of hadronic and nuclear collisions at high energies. These components are members of hadronic application modules that have been developed with the help of the NiMax system. Given report is served as an early release of the NiMax manual mainly for model component users

  18. Implementing a Flipped Classroom Approach in a University Numerical Methods Mathematics Course

    Science.gov (United States)

    Johnston, Barbara M.

    2017-01-01

    This paper describes and analyses the implementation of a "flipped classroom" approach, in an undergraduate mathematics course on numerical methods. The approach replaced all the lecture contents by instructor-made videos and was implemented in the consecutive years 2014 and 2015. The sequential case study presented here begins with an…

  19. Building bridges connections and challenges in modern approaches to numerical partial differential equations

    CERN Document Server

    Brezzi, Franco; Cangiani, Andrea; Georgoulis, Emmanuil

    2016-01-01

    This volume contains contributed survey papers from the main speakers at the LMS/EPSRC Symposium “Building bridges: connections and challenges in modern approaches to numerical partial differential equations”. This meeting took place in July 8-16, 2014, and its main purpose was to gather specialists in emerging areas of numerical PDEs, and explore the connections between the different approaches. The type of contributions ranges from the theoretical foundations of these new techniques, to the applications of them, to new general frameworks and unified approaches that can cover one, or more than one, of these emerging techniques.

  20. Determination of dopaminergic prodrugs by high-performance liquid chromatography followed by post-column ion-pair extraction

    NARCIS (Netherlands)

    Haas, M; Moolenaar, Frits; Kluppel, A.C A; Dijkstra, D.; Meijer, D.K F; de Zeeuw, D

    1997-01-01

    One possibility to optimize the therapeutic application of dopaminergic compounds with a catechol function is the reversible protection of this moiety using a prodrug approach. Important features in this respect are a proper chemical stability in the gastrointestinal tract, an adequate release rate

  1. Circumvention of P-gp and MRP2 mediated efflux of lopinavir by a histidine based dipeptide prodrug.

    Science.gov (United States)

    Mandal, Abhirup; Pal, Dhananjay; Mitra, Ashim K

    2016-10-15

    This study was aimed to develop a novel Histidine-Leucine-Lopinavir (His-Leu-LPV) dipeptide prodrug and evaluate its potential for circumvention of P-gp and MRP2-mediated efflux of lopinavir (LPV) indicated for HIV-1 infection. His-Leu-LPV was synthesized following esterification of hydroxyl group of LPV and was identified by (1)H NMR and LCMS/MS techniques. Aqueous solubility, stability and cell cytotoxicity of prodrug was determined. Uptake and permeability studies were carried out using P-gp (MDCK-MDR1) and MRP2 (MDCK-MRP2) transfected cell lines. To further delineate prodrug uptake, prodrug interaction with influx transporters (PepT1 and PHT1) was determined. Enzymatic hydrolysis and reconversion of His-Leu-LPV to LPV was examined using Caco-2 cell homogenates. Aqueous solubility generated by the prodrug was markedly higher relative to unmodified LPV. Importantly, His-Leu-LPV displayed significantly lower affinity towards P-gp and MRP2 as evident from higher uptake and transport rates. [3H]-GlySar and [3H]-l-His uptake receded to approximately 30% in the presence of His-Leu-LPV supporting the PepT1/PHT1 mediated uptake process. A steady regeneration of LPV and Leu-LPV in Caco-2 cell homogenates indicated His-Leu-LPV undergoes both esterase and peptidase-mediated hydrolysis. Histidine based dipeptide prodrug approach can be an alternative strategy to improve LPV absorption across poorly permeable intestinal barrier. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. A new numerical approach for uniquely solvable exterior Riemann-Hilbert problem on region with corners

    Science.gov (United States)

    Zamzamir, Zamzana; Murid, Ali H. M.; Ismail, Munira

    2014-06-01

    Numerical solution for uniquely solvable exterior Riemann-Hilbert problem on region with corners at offcorner points has been explored by discretizing the related integral equation using Picard iteration method without any modifications to the left-hand side (LHS) and right-hand side (RHS) of the integral equation. Numerical errors for all iterations are converge to the required solution. However, for certain problems, it gives lower accuracy. Hence, this paper presents a new numerical approach for the problem by treating the generalized Neumann kernel at LHS and the function at RHS of the integral equation. Due to the existence of the corner points, Gaussian quadrature is employed which avoids the corner points during numerical integration. Numerical example on a test region is presented to demonstrate the effectiveness of this formulation.

  3. Comparison of numerical approaches to solve a Poincare-covariant Faddeev equation

    International Nuclear Information System (INIS)

    Alkofer, R.; Eichmann, G.; Krassnigg, A.; Schwinzerl, M.

    2006-01-01

    Full text: The quark core of Baryons can be described with the help of the numerical solution of the Poincare-Faddeev equation. Hereby the used elements, as e.g. the quark propagator are taken from non-perturbative studies of Landau gauge QCD. Different numerical approaches to solve in this way the relativistic three quark problem are compared and benchmarked results for the efficiency of different algorithms are presented. (author)

  4. Copper-free click-chemistry platform to functionalize cisplatin prodrugs.

    Science.gov (United States)

    Pathak, Rakesh K; McNitt, Christopher D; Popik, Vladimir V; Dhar, Shanta

    2014-06-02

    The ability to rationally design and construct a platform technology to develop new platinum(IV) [Pt(IV)] prodrugs with functionalities for installation of targeting moieties, delivery systems, fluorescent reporters from a single precursor with the ability to release biologically active cisplatin by using well-defined chemistry is critical for discovering new platinum-based therapeutics. With limited numbers of possibilities considering the sensitivity of Pt(IV) centers, we used a strain-promoted azide-alkyne cycloaddition approach to provide a platform, in which new functionalities can easily be installed on cisplatin prodrugs from a single Pt(IV) precursor. The ability of this platform to be incorporated in nanodelivery vehicle and conjugation to fluorescent reporters were also investigated. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Effect of Simvastatin Prodrug on Experimental Periodontitis.

    Science.gov (United States)

    Bradley, Aaron D; Zhang, Yijia; Jia, Zhenshan; Zhao, Gang; Wang, Xiaobei; Pranke, Laura; Schmid, Marian J; Wang, Dong; Reinhardt, Richard A

    2016-05-01

    Local application of statins has shown potential in preventing and regenerating bone loss associated with experimental periodontitis. This study evaluates the effect of a novel simvastatin (SIM) prodrug (capable of delivering high doses to periodontitis inflammatory lesion and cells) on experimental periodontitis bone loss and inflammation. Forty mature female Sprague Dawley rats were subjected to ligature-induced experimental periodontitis between maxillary first and second molars (M1-M2). Equal groups were treated with three weekly doses of: 1) prodrug carrier alone (mPEG); 2) 0.5 mg SIM dose equivalent in carrier (SIM/SIM-mPEG); 3) 1.0 mg SIM/SIM-mPEG; 4) 1.5 mg SIM/SIM-mPEG; or 5) ligature alone. Contralateral molars served as unmanipulated controls. Four weeks after initiation of periodontitis, animals were euthanized, the M1-M2 interproximal was evaluated with microcomputed tomography and histology, and data were analyzed with one-way analysis of variance. Ligature alone caused a mean bone loss of 1.01 ± 0.06 mm from the cemento-enamel junction, whereas all doses of SIM/SIM-mPEG reduced bone loss, especially 1.5 mg SIM/SIM-mPEG (0.68 ± 0.05 mm, P periodontitis bone loss and inflammation in rats.

  6. Transdermal delivery and cutaneous targeting of antivirals using a penetration enhancer and lysolipid prodrugs.

    Science.gov (United States)

    Diblíková, Denisa; Kopečná, Monika; Školová, Barbora; Krečmerová, Marcela; Roh, Jaroslav; Hrabálek, Alexandr; Vávrová, Kateřina

    2014-04-01

    In this work, we investigate prodrug and enhancer approaches for transdermal and topical delivery of antiviral drugs belonging to the 2,6-diaminopurine acyclic nucleoside phosphonate (ANP) group. Our question was whether we can differentiate between transdermal and topical delivery, i.e., to control the delivery of a given drug towards either systemic absorption or retention in the skin. The in vitro transdermal delivery and skin concentrations of seven antivirals, including (R)- and (S)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine ((S)-HPMPDAP), its 8-aza analog, and their cyclic and hexadecyloxypropyl (HDP) prodrugs, was investigated with and without the penetration enhancer dodecyl-6-(dimethylamino)hexanoate (DDAK) using human skin. The ability of ANPs to cross the human skin barrier was very low (0.5-1.4 nmol/cm(2)/h), and the majority of the compounds were found in the stratum corneum, the uppermost skin layer. The combination of antivirals and the penetration enhancer DDAK proved to be a viable approach for transdermal delivery, especially in case of (R)-PMPDAP, an anti-HIV effective drug (30.2 ± 2.3 nmol/cm(2)/h). On the other hand, lysophospholipid-like HDP prodrugs, e.g., HDP-(S)-HPMPDAP, reached high concentrations in viable epidermis without significant systemic absorption. By using penetration enhancers or lysolipid prodrugs, it is possible to effectively target systemic diseases by the transdermal route or to target cutaneous pathologies by topical delivery.

  7. Estimation of flushing time in a monsoonal estuary using observational and numerical approaches

    Digital Repository Service at National Institute of Oceanography (India)

    Manoj, N.T.

    and numerical model simulations to correlate TF with monthly mean river discharges. The power regression equation derived from FOS (numerical model) showed good statistical fit with data (r=-0.997 (-1.0)) for any given river discharge compared... was to calculate the TF in the Mandovi during three different seasons in a year. For this purpose, we adopted two approaches, first the computation of TF from FOS. The application of H2N-Model was another approach to calculate the TF in the estuary. The FWF...

  8. A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer.

    Science.gov (United States)

    Levy, Oren; Brennen, W Nathaniel; Han, Edward; Rosen, David Marc; Musabeyezu, Juliet; Safaee, Helia; Ranganath, Sudhir; Ngai, Jessica; Heinelt, Martina; Milton, Yuka; Wang, Hao; Bhagchandani, Sachin H; Joshi, Nitin; Bhowmick, Neil; Denmeade, Samuel R; Isaacs, John T; Karp, Jeffrey M

    2016-06-01

    Despite considerable advances in prostate cancer research, there is a major need for a systemic delivery platform that efficiently targets anti-cancer drugs to sites of disseminated prostate cancer while minimizing host toxicity. In this proof-of-principle study, human mesenchymal stem cells (MSCs) were loaded with poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) that encapsulate the macromolecule G114, a thapsigargin-based prostate specific antigen (PSA)-activated prodrug. G114-particles (∼950 nm in size) were internalized by MSCs, followed by the release of G114 as an intact prodrug from loaded cells. Moreover, G114 released from G114 MP-loaded MSCs selectively induced death of the PSA-secreting PCa cell line, LNCaP. Finally, G114 MP-loaded MSCs inhibited tumor growth when used in proof-of-concept co-inoculation studies with CWR22 PCa xenografts, suggesting that cell-based delivery of G114 did not compromise the potency of this pro-drug in-vitro or in-vivo. This study demonstrates a potentially promising approach to assemble a cell-based drug delivery platform, which inhibits cancer growth in-vivo without the need of genetic engineering. We envision that upon achieving efficient homing of systemically infused MSCs to cancer sites, this MSC-based platform may be developed into an effective, systemic 'Trojan Horse' therapy for targeted delivery of therapeutic agents to sites of metastatic PCa. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Novel Polymeric Prodrugs of Valproic Acid as Anti- Epilepsy Drugs ...

    African Journals Online (AJOL)

    Epilepsy Drugs: Synthesis, Characterization and In-vitro ... The release of VPA from polymeric prodrugs was studied using cellophane ... pharmacokinetics and accessibility in market [8]. ..... between the drug and polymer chain can affect.

  10. Synthesis, characterization and pharmacological evaluation of amide prodrugs of Flurbiprofen

    International Nuclear Information System (INIS)

    Mishra, Ashutosh; Veerasamy, Ravichandran; Jain, Prateek Kumar; Dixit, Vinod Kumar; Agrawal, Ram Kishor

    2008-01-01

    Flurbiprofen (FB) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study was aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of FB were synthesized by amidation with ethyl esters of amino acids, namely, glycine, L-phenylalanine, L-tryptophan, L-valine, L-isoleucine, L-alanine, L-leucine, L-glutamic acid, L-aspartic acid and β alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for bioavailability studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, antiinflammatory activities were obtained in all cases as compared to FB. Among synthesized prodrugs AR-9, AR-10 and AR-2 showing excellent pharmacological response and encouraging hydrolysis rate both in (Simulated Intestinal Fluid) SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent resulted in enhanced partition coefficient but diminished dissolution and hydrolysis rate. Such prodrugs can be considered for sustained release purpose. (author)

  11. Synthesis, characterization and pharmacological evaluation of amide prodrugs of Flurbiprofen

    Energy Technology Data Exchange (ETDEWEB)

    Mishra, Ashutosh; Veerasamy, Ravichandran; Jain, Prateek Kumar; Dixit, Vinod Kumar; Agrawal, Ram Kishor [Dr. H. S. Gour Vishwavidyalaya, Sagar (India). Dept. of Pharmaceutical Sciences. Pharmaceutical Chemistry Research Lab.]. E-mail: dragrawal2001@yahoo.co.in

    2008-07-01

    Flurbiprofen (FB) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study was aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of FB were synthesized by amidation with ethyl esters of amino acids, namely, glycine, L-phenylalanine, L-tryptophan, L-valine, L-isoleucine, L-alanine, L-leucine, L-glutamic acid, L-aspartic acid and {beta} alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for bioavailability studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, antiinflammatory activities were obtained in all cases as compared to FB. Among synthesized prodrugs AR-9, AR-10 and AR-2 showing excellent pharmacological response and encouraging hydrolysis rate both in (Simulated Intestinal Fluid) SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent resulted in enhanced partition coefficient but diminished dissolution and hydrolysis rate. Such prodrugs can be considered for sustained release purpose. (author)

  12. Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery.

    Science.gov (United States)

    Pan, Dipanjan; Pham, Christine T N; Weilbaecher, Katherine N; Tomasson, Michael H; Wickline, Samuel A; Lanza, Gregory M

    2016-01-01

    Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a 'magic bullet' to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies equally well for vascular constrained lipid-encapsulated particles and micelles the size of proteins that penetrate through naturally fenestrated endothelium in the bone marrow or thin-walled venules of an inflamed microcirculation. At one time Nanomedicine was considered a 'Grail Quest' by its loyal opposition and even many in the field adsorbing the pains of a long-learning curve about human biology and particles. However, Nanomedicine with innovations like Sn2 phospholipid prodrugs has finally made 'made the turn' toward meaningful translational success. © 2015 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals, Inc.

  13. NUMERICAL SIMULATION OF ELECTRICAL IMPEDANCE TOMOGRAPHY PROBLEM AND STUDY OF APPROACH BASED ON FINITE VOLUME METHOD

    Directory of Open Access Journals (Sweden)

    Ye. S. Sherina

    2014-01-01

    Full Text Available This research has been aimed to carry out a study of peculiarities that arise in a numerical simulation of the electrical impedance tomography (EIT problem. Static EIT image reconstruction is sensitive to a measurement noise and approximation error. A special consideration has been given to reducing of the approximation error, which originates from numerical implementation drawbacks. This paper presents in detail two numerical approaches for solving EIT forward problem. The finite volume method (FVM on unstructured triangular mesh is introduced. In order to compare this approach, the finite element (FEM based forward solver was implemented, which has gained the most popularity among researchers. The calculated potential distribution with the assumed initial conductivity distribution has been compared to the analytical solution of a test Neumann boundary problem and to the results of problem simulation by means of ANSYS FLUENT commercial software. Two approaches to linearized EIT image reconstruction are discussed. Reconstruction of the conductivity distribution is an ill-posed problem, typically requiring a large amount of computation and resolved by minimization techniques. The objective function to be minimized is constructed of measured voltage and calculated boundary voltage on the electrodes. A classical modified Newton type iterative method and the stochastic differential evolution method are employed. A software package has been developed for the problem under investigation. Numerical tests were conducted on simulated data. The obtained results could be helpful to researches tackling the hardware and software issues for medical applications of EIT.

  14. The simulation of solute transport: An approach free of numerical dispersion

    International Nuclear Information System (INIS)

    Carrera, J.; Melloni, G.

    1987-01-01

    The applicability of most algorithms for simulation of solute transport is limited either by instability or by numerical dispersion, as seen by a review of existing methods. A new approach is proposed that is free of these two problems. The method is based on the mixed Eulerian-Lagrangian formulation of the mass-transport problem, thus ensuring stability. Advection is simulated by a variation of reverse-particle tracking that avoids the accumulation of interpolation errors, thus preventing numerical dispersion. The algorithm has been implemented in a one-dimensional code. Excellent results are obtained, in comparison with an analytical solution. 36 refs., 14 figs., 1 tab

  15. Effect of charged line defects on conductivity in graphene: Numerical Kubo and analytical Boltzmann approaches

    DEFF Research Database (Denmark)

    Radchenko, T. M.; Shylau, A. A.; Zozoulenko, I. V.

    2013-01-01

    . A numerical study of electronic transport is performed by means of a time-dependent real-space Kubo approach in honeycomb lattices containing millions of carbon atoms, capturing the linear response of realistic size systems in the highly disordered regime. Our numerical calculations are complemented...... with the Kubo calculations. In the strong scattering regime, the conductivity is found to be a sublinear function of electronic density and weakly dependent on the Thomas-Fermi screening wavelength. We attribute this atypical behavior to the extended nature of one-dimensional charged defects. Our results...

  16. Effects of vehicles and prodrug properties and their interactions on the delivery of 6-mercaptopurine through skin: bisacyloxymethyl-6-mercaptopurine prodrugs.

    Science.gov (United States)

    Waranis, R P; Sloan, K B

    1987-08-01

    A series of S6,9-bisacyloxymethyl-6-mercaptopurine (6,9-bis-6-MP) prodrug derivatives was synthesized and characterized. The solubilities of the derivatives in solvents (vehicles), which exhibited a wide range of polarities from water to oleic acid, were measured. The abilities of the prodrugs to deliver 6-mercaptopurine (6-MP) from the vehicles have also been determined, and experimental fluxes and permeability coefficients (Kp) have been calculated for a large number of prodrug: vehicle combinations. Generally the best prodrugs of the series in terms of delivering 6-MP, regardless of the vehicle, were the first two members--the bisacetyl- and the bispropionyloxymethyl-6-mercaptopurine prodrugs. This result has been attributed mainly to the increased water solubility of these two prodrugs compared with that of 6-MP and the other prodrugs, since all of the prodrugs are much more lipid soluble than 6-MP. For three vehicles--isopropyl myristate, propylene glycol, and water--there was a good correlation between log experimental Kp for the delivery of 6-MP by the prodrugs from those vehicles and the theoretical solubility parameters of the prodrugs. The stabilities of the bisacetyl-(2), bisproprionyl-(3), and bisbutyryloxymethyl-6-mercaptopurine (4) derivatives were determined in buffer and in buffer containing enzymes leached from the dermis. Prodrug 2 was more stable than 3 or 4 in the buffer containing the enzymes, while 4 was more stable than 2 or 3 in the plain buffer.

  17. Stimuli-responsive PEGylated prodrugs for targeted doxorubicin delivery

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Minghui; Qian, Junmin, E-mail: jmqian@mail.xjtu.edu.cn; Liu, Xuefeng; Liu, Ting; Wang, Hongjie

    2015-05-01

    In recent years, stimuli-sensitive prodrugs have been extensively studied for the rapid “burst” release of antitumor drugs to enhance chemotherapeutic efficiency. In this study, a novel stimuli-sensitive prodrug containing galactosamine as a targeting moiety, poly(ethylene glycol)–doxorubicin (PEG–DOX) conjugate, was developed for targeting HepG2 human liver cancer cells. To obtain the PEG–DOX conjugate, both galactosamine-decorated poly(ethylene glycol) aldehyde (Gal-PEG-CHO) and methoxy poly(ethylene glycol) aldehyde (mPEG-CHO) were firstly synthesized and functionalized with dithiodipropionate dihydrazide (TPH) through direct reductive amination via Schiff's base formation, and then DOX molecules were chemically conjugated to the hydrazide end groups of TPH-functionalized Gal-/m-PEG chains via pH-sensitive hydrazone linkages. The chemical structures of TPH-functionalized PEG and PEG–DOX prodrug were confirmed by {sup 1}H NMR analysis. The PEG–DOX conjugate could self-assemble into spherical nanomicelles with a mean diameter of 140 nm, as indicated by transmission electron microscopy and dynamic light scattering. The drug loading content and loading efficiency in the prodrug nanomicelles were as high as 20 wt.% and 75 wt.%, respectively. In vitro drug release studies showed that DOX was released rapidly from the prodrug nanomicelles at the intracellular levels of pH and reducing agent. Cellular uptake and MTT experiments demonstrated that the galactosamine-decorated prodrug nanomicelles were more efficiently internalized into HepG2 cells via a receptor-mediated endocytosis process and exhibited a higher toxicity, compared with pristine prodrug nanomicelles. These results suggest that the novel Gal-PEG–DOX prodrug nanomicelles have tremendous potential for targeted liver cancer therapy. - Highlights: • A novel stimuli-responsive PEGylated prodrugs is synthesized. • PEGylated prodrugs can self-assemble into spherical nanoparticles (140 nm

  18. Numerical simulation of a plate-fin heat exchanger with offset fins using porous media approach

    Science.gov (United States)

    Juan, Du; Hai-Tao, Zhao

    2018-03-01

    In this paper, the study was focused on a double flow plate-fin heat exchanger (PFHE) whose heat transfer element was offset staggered fin. Numerical simulations have been carried out to investigate the thermodynamic characteristics of a full-size PFHE via the porous media approach. Based on the numerical model, the effects of the dynamic viscosity and the locations of the inlet and outlet tubes on flow distribution and pressure drop of the PFHE were studied. The results showed that flow distribution of the PFHE was improved by increasing the dynamic viscosity. Therefore, the relationship between flow distribution and pressure drop was analyzed under various inlet velocity, and a correlation among flow distribution, pressure drop, and Reynolds number was derived. Finally, the middle-based strategy was proposed and numerically verified to improve flow distribution of the PFHE.

  19. Electromagnetic scattering problems -Numerical issues and new experimental approaches of validation

    Energy Technology Data Exchange (ETDEWEB)

    Geise, Robert; Neubauer, Bjoern; Zimmer, Georg [University of Braunschweig, Institute for Electromagnetic Compatibility, Schleinitzstrasse 23, 38106 Braunschweig (Germany)

    2015-03-10

    Electromagnetic scattering problems, thus the question how radiated energy spreads when impinging on an object, are an essential part of wave propagation. Though the Maxwell’s differential equations as starting point, are actually quite simple,the integral formulation of an object’s boundary conditions, respectively the solution for unknown induced currents can only be solved numerically in most cases.As a timely topic of practical importance the scattering of rotating wind turbines is discussed, the numerical description of which is still based on rigorous approximations with yet unspecified accuracy. In this context the issue of validating numerical solutions is addressed, both with reference simulations but in particular with the experimental approach of scaled measurements. For the latter the idea of an incremental validation is proposed allowing a step by step validation of required new mathematical models in scattering theory.

  20. Implementing a flipped classroom approach in a university numerical methods mathematics course

    Science.gov (United States)

    Johnston, Barbara M.

    2017-05-01

    This paper describes and analyses the implementation of a 'flipped classroom' approach, in an undergraduate mathematics course on numerical methods. The approach replaced all the lecture contents by instructor-made videos and was implemented in the consecutive years 2014 and 2015. The sequential case study presented here begins with an examination of the attitudes of the 2014 cohort to the approach in general as well as analysing their use of the videos. Based on these responses, the instructor makes a number of changes (for example, the use of 'cloze' summary notes and the introduction of an extra, optional tutorial class) before repeating the 'flipped classroom' approach the following year. The attitudes to the approach and the video usage of the 2015 cohort are then compared with the 2014 cohort and further changes that could be implemented for the next cohort are suggested.

  1. Prodrugs designed to discriminate pathological (tumour) and physiological (normal tissue) hypoxia

    International Nuclear Information System (INIS)

    Wilson, W.R.; Patterson, A.V.

    2003-01-01

    There is now abundant evidence that hypoxic contributes to treatment failure in radiation therapy. As a target for therapeutic intervention, hypoxia is especially attractive because it is a common feature of most human tumours and therefore a potential 'pan target' across many tumour types. However, attempts to exploit hypoxia face the problem that oxygen concentrations in some normal tissues are also heterogeneous and that O 2 distributions in tumours and normal tissues overlap. Simply adjusting the K value (O 2 concentration for 50% inhibition of activation) does not provide a satisfactory solution. Bioreductive drugs like tirapazamine with high K values are activated significantly in several normal tissues, while nitro compounds and quinones with low K values spare the hypoxic tumour cells at 'intermediate' O 2 tensions (1-10 mM O 2 ) which are considered to be major contributors to tumour radioresistance. A potential strategy for overcoming this dilemma is to design prodrugs that are activated only at very low K values, but give relatively stable cytotoxic metabolites capable of diffusing to cells at higher O 2 concentrations. This approach redefines the therapeutic target as cells adjacent to zones of pathological hypoxia ( 2 ), providing discrimination from physiological hypoxia in normal tissues. Detecting bioreductive prodrugs capable of providing bystander killing of this kind is not straightforward. We have adapted a multicellular layer (MCL) co-culture model for quantifying bystander effects in GDEPT (Wilson et al., Cancer Res., 62: 1425-1432, 2002), and have used this to measure bystander effects of hypoxia-activated prodrugs. This model uses differences in metabolic activation of bioreductive drugs between A459 cell lines with low and high cytochrome P450 reductase activity, rather than O 2 gradients, to effect localised prodrug activation. It shows that TPZ and the nitroimidazole RSU-1069 have little or no bystander effect, but that dinitrobenzamide

  2. Numerical solution of the full potential equation using a chimera grid approach

    Science.gov (United States)

    Holst, Terry L.

    1995-01-01

    A numerical scheme utilizing a chimera zonal grid approach for solving the full potential equation in two spatial dimensions is described. Within each grid zone a fully-implicit approximate factorization scheme is used to advance the solution one interaction. This is followed by the explicit advance of all common zonal grid boundaries using a bilinear interpolation of the velocity potential. The presentation is highlighted with numerical results simulating the flow about a two-dimensional, nonlifting, circular cylinder. For this problem, the flow domain is divided into two parts: an inner portion covered by a polar grid and an outer portion covered by a Cartesian grid. Both incompressible and compressible (transonic) flow solutions are included. Comparisons made with an analytic solution as well as single grid results indicate that the chimera zonal grid approach is a viable technique for solving the full potential equation.

  3. An efficient approach for computing the geometrical optics field reflected from a numerically specified surface

    Science.gov (United States)

    Mittra, R.; Rushdi, A.

    1979-01-01

    An approach for computing the geometrical optic fields reflected from a numerically specified surface is presented. The approach includes the step of deriving a specular point and begins with computing the reflected rays off the surface at the points where their coordinates, as well as the partial derivatives (or equivalently, the direction of the normal), are numerically specified. Then, a cluster of three adjacent rays are chosen to define a 'mean ray' and the divergence factor associated with this mean ray. Finally, the ampilitude, phase, and vector direction of the reflected field at a given observation point are derived by associating this point with the nearest mean ray and determining its position relative to such a ray.

  4. Optimal control approaches for aircraft conflict avoidance using speed regulation : a numerical study

    OpenAIRE

    Cellier , Loïc; Cafieri , Sonia; Messine , Frederic

    2013-01-01

    International audience; In this paper a numerical study is provided to solve the aircraft conflict avoidance problem through velocity regulation maneuvers. Starting from optimal controlbased model and approaches in which aircraft accelerations are the controls, and by applying the direct shooting technique, we propose to study two different largescale nonlinear optimization problems. In order to compare different possibilities of implementation, two environments (AMPL and MATLAB) and determin...

  5. Characterisation of large catastrophic landslides using an integrated field, remote sensing and numerical modelling approach

    OpenAIRE

    Wolter, Andrea Elaine

    2014-01-01

    I apply a forensic, multidisciplinary approach that integrates engineering geology field investigations, engineering geomorphology mapping, long-range terrestrial photogrammetry, and a numerical modelling toolbox to two large rock slope failures to study their causes, initiation, kinematics, and dynamics. I demonstrate the significance of endogenic and exogenic processes, both separately and in concert, in contributing to landscape evolution and conditioning slopes for failure, and use geomor...

  6. Information fusion in signal and image processing major probabilistic and non-probabilistic numerical approaches

    CERN Document Server

    Bloch, Isabelle

    2010-01-01

    The area of information fusion has grown considerably during the last few years, leading to a rapid and impressive evolution. In such fast-moving times, it is important to take stock of the changes that have occurred. As such, this books offers an overview of the general principles and specificities of information fusion in signal and image processing, as well as covering the main numerical methods (probabilistic approaches, fuzzy sets and possibility theory and belief functions).

  7. Prodrugs activated by reactive oxygen species for use in the treatment of inflammatory diseases and cancer

    DEFF Research Database (Denmark)

    2018-01-01

    Prodrugs activated predominantly or exclusively in inflammatory tissue, more particularly prodrugs of methotrexate and derivatives thereof, which are selectively activated by Reactive Oxygen Species (ROS) in inflammatory tissues associated with cancer and inflammatory diseases, as well as method...

  8. 1-Arylsulfonyl-2-(Pyridylmethylsulfinyl) Benzimidazoles as New Proton Pump Inhibitor Prodrugs

    Science.gov (United States)

    Shin, Jai Moo; Sachs, George; Cho, Young-moon; Garst, Michael

    2010-01-01

    New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized. These prodrugs provided longer residence time of an effective PPI plasma concentration, resulting in better gastric acid inhibition. PMID:20032890

  9. Prodrugs of Pyrazolo[3,4-d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model.

    Science.gov (United States)

    Vignaroli, Giulia; Iovenitti, Giulia; Zamperini, Claudio; Coniglio, Federica; Calandro, Pierpaolo; Molinari, Alessio; Fallacara, Anna Lucia; Sartucci, Andrea; Calgani, Alessia; Colecchia, David; Mancini, Andrea; Festuccia, Claudio; Dreassi, Elena; Valoti, Massimo; Musumeci, Francesca; Chiariello, Mario; Angelucci, Adriano; Botta, Maurizio; Schenone, Silvia

    2017-07-27

    Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a-8a and 9a-e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME studies demonstrated for the most promising prodrugs a better aqueous solubility, a favorable hydrolysis in human and murine serum, and an increased ability to cross cell membranes with respect to the parental drugs, explaining their better 24 h in vitro cytotoxicity against human glioblastoma U87 cell line. Finally, the 4-4a couple of drug/prodrug was also evaluated in vivo, revealing a profitable pharmacokinetic profile of the prodrug associated with a good efficacy. The application of the prodrug approach demonstrated to be a successful strategy for improving aqueous solubility of the parental drugs, determining a positive impact also in their biological efficacy.

  10. Preface of "The Second Symposium on Border Zones Between Experimental and Numerical Application Including Solution Approaches By Extensions of Standard Numerical Methods"

    Science.gov (United States)

    Ortleb, Sigrun; Seidel, Christian

    2017-07-01

    In this second symposium at the limits of experimental and numerical methods, recent research is presented on practically relevant problems. Presentations discuss experimental investigation as well as numerical methods with a strong focus on application. In addition, problems are identified which require a hybrid experimental-numerical approach. Topics include fast explicit diffusion applied to a geothermal energy storage tank, noise in experimental measurements of electrical quantities, thermal fluid structure interaction, tensegrity structures, experimental and numerical methods for Chladni figures, optimized construction of hydroelectric power stations, experimental and numerical limits in the investigation of rain-wind induced vibrations as well as the application of exponential integrators in a domain-based IMEX setting.

  11. Conceptual Model and Numerical Approaches for Unsaturated Zone Flow and Transport

    International Nuclear Information System (INIS)

    H.H. Liu

    2004-01-01

    The purpose of this model report is to document the conceptual and numerical models used for modeling unsaturated zone (UZ) fluid (water and air) flow and solute transport processes. This work was planned in ''Technical Work Plan for: Unsaturated Zone Flow Model and Analysis Report Integration'' (BSC 2004 [DIRS 169654], Sections 1.2.5, 2.1.1, 2.1.2 and 2.2.1). The conceptual and numerical modeling approaches described in this report are mainly used for models of UZ flow and transport in fractured, unsaturated rock under ambient conditions. Developments of these models are documented in the following model reports: (1) UZ Flow Model and Submodels; (2) Radionuclide Transport Models under Ambient Conditions. Conceptual models for flow and transport in unsaturated, fractured media are discussed in terms of their applicability to the UZ at Yucca Mountain. The rationale for selecting the conceptual models used for modeling of UZ flow and transport is documented. Numerical approaches for incorporating these conceptual models are evaluated in terms of their representation of the selected conceptual models and computational efficiency; and the rationales for selecting the numerical approaches used for modeling of UZ flow and transport are discussed. This report also documents activities to validate the active fracture model (AFM) based on experimental observations and theoretical developments. The AFM is a conceptual model that describes the fracture-matrix interaction in the UZ of Yucca Mountain. These validation activities are documented in Section 7 of this report regarding use of an independent line of evidence to provide additional confidence in the use of the AFM in the UZ models. The AFM has been used in UZ flow and transport models under both ambient and thermally disturbed conditions. Developments of these models are documented

  12. Colon-specific prodrugs of 5-radioiodo-2'-deoxyuridine

    International Nuclear Information System (INIS)

    Baranowska-Kortylewicz, J.; Kortylewicz, Z.P.; Hoffman, D.; Winoto, A.; Lai, J.; Dalrymple, G.V.

    1996-01-01

    Two glycoside-based prodrugs, 125 IUdR-5'-β-D-glucopyranoside and 125 IUdR-5'-β-D-galactopyranoside, were synthesized. This selection was dictated by the abundance of appropriate enzymes in the GI tract of mice and similar levels of β-D-glycosidases in human and rodent large intestine. Studies to establish the ability of colonic microflora to release 125 IUdR were conducted in vitro and in Swiss Webster mice. Both prodrugs released 125 IUdR in the presence of the corresponding enzymes or the GI content homogenates in vitro, and in vivo. Luminal enzymes in the proximal and distal small intestine in mice degraded less than 10% of each prodrug whereas enzymes from the colonic/caecal lumen of mice released nearly 100% of 125 IUdR. 125 IUdR freed by bacterial glycosidases was stable in the GI content. No significant amounts of other metabolites or deiodination products were observed. Total radioactivity recovered as by-products was less than 10%. The efflux of prodrugs from the GI tract after oral administration in mice was slow and limited. Unlike 125 IUdR, prodrugs were not dehalogenated in vivo as indicated by biodistribution and imaging studies. (orig.)

  13. Numerical and experimental approaches to simulate soil clogging in porous media

    Science.gov (United States)

    Kanarska, Yuliya; LLNL Team

    2012-11-01

    Failure of a dam by erosion ranks among the most serious accidents in civil engineering. The best way to prevent internal erosion is using adequate granular filters in the transition areas where important hydraulic gradients can appear. In case of cracking and erosion, if the filter is capable of retaining the eroded particles, the crack will seal and the dam safety will be ensured. A finite element numerical solution of the Navier-Stokes equations for fluid flow together with Lagrange multiplier technique for solid particles was applied to the simulation of soil filtration. The numerical approach was validated through comparison of numerical simulations with the experimental results of base soil particle clogging in the filter layers performed at ERDC. The numerical simulation correctly predicted flow and pressure decay due to particle clogging. The base soil particle distribution was almost identical to those measured in the laboratory experiment. To get more precise understanding of the soil transport in granular filters we investigated sensitivity of particle clogging mechanisms to various aspects such as particle size ration, the amplitude of hydraulic gradient, particle concentration and contact properties. By averaging the results derived from the grain-scale simulations, we investigated how those factors affect the semi-empirical multiphase model parameters in the large-scale simulation tool. The Department of Homeland Security Science and Technology Directorate provided funding for this research.

  14. pH-sensitive pHluorins as a molecular sensor for in situ monitoring of enzyme-catalyzed prodrug activation.

    Science.gov (United States)

    Liu, Hui; Cao, Xiaodan; Wang, Ping; Ma, Xingyuan

    2017-07-01

    This work examines the feasibility of using a pH-sensitive fluorescent protein as a molecular reporter for enzyme-catalyzed prodrug activation reaction. Specifically, a ratiometric pHluorins was examined for detection of the activity of horseradish peroxidase (HRP) for the activation of indole-3-acetic acid. The pHluorins and HRP were conjugated chemically, forming a biocatalyst with a self-reporting function. Results showed that the characteristic fluorescence intensity ratio of the conjugate shifted from 1.47 to 1.40 corresponding to the progress of the prodrug activation reaction. The effectiveness of applying the conjugate for inhibition of the growth of Bcap-37 cells was also demonstrated simultaneously with reaction monitoring. The results reveal a very promising approach to realizing in situ monitoring of enzyme activities based on pH shifting for enzyme-based prodrug therapy applications. © 2016 International Union of Biochemistry and Molecular Biology, Inc.

  15. Prolonged naproxen joint residence time after intra-articular injection of lipophilic solutions comprising a naproxen glycolamide ester prodrug in the rat

    DEFF Research Database (Denmark)

    Thing, Mette; Lu, Yi; Agårdh, Li

    2013-01-01

    time. Two oils, medium-chain triglycerides and castor oil, differing with respect to viscosity were tested. After intra-articular administration of oil prodrug solutions, a significant increase in the time to maximum naproxen serum concentration from around 40 to 245min, an increase in the MRTj from......Intra-articular injection of oil solutions of lipophilic prodrugs that rapidly degrade to their parent compound in synovial fluid may constitute a feasible approach to increase the joint residence time of non-steroidal anti-inflammatory drugs. In this in vivo study, oil solutions of the N......,N-diethyl glycolamide ester prodrug of naproxen (16mg/ml) were injected into the rat knee joint by dosing 6μl formulation per 100g body weight. The sustained release properties were compared to those of intra-articularly injected aqueous and oil solutions of naproxen by monitoring the naproxen serum concentrations over...

  16. Numerical Approach for Goaf-Side Entry Layout and Yield Pillar Design in Fractured Ground Conditions

    Science.gov (United States)

    Jiang, Lishuai; Zhang, Peipeng; Chen, Lianjun; Hao, Zhen; Sainoki, Atsushi; Mitri, Hani S.; Wang, Qingbiao

    2017-11-01

    Entry driven along goaf-side (EDG), which is the development of an entry of the next longwall panel along the goaf-side and the isolation of the entry from the goaf with a small-width yield pillar, has been widely employed in China over the past several decades . The width of such a yield pillar has a crucial effect on EDG layout in terms of the ground control, isolation effect and resource recovery rate. Based on a case study, this paper presents an approach for evaluating, designing and optimizing EDG and yield pillar by considering the results from numerical simulations and field practice. To rigorously analyze the ground stability, the numerical study begins with the simulation of goaf-side stress and ground conditions. Four global models with identical conditions, except for the width of the yield pillar, are built, and the effect of pillar width on ground stability is investigated by comparing aspects of stress distribution, failure propagation, and displacement evolution during the entire service life of the entry. Based on simulation results, the isolation effect of the pillar acquired from field practice is also considered. The suggested optimal yield pillar design is validated using a field test in the same mine. Thus, the presented numerical approach provides references and can be utilized for the evaluation, design and optimization of EDG and yield pillars under similar geological and geotechnical circumstances.

  17. A numerical spectral approach to solve the dislocation density transport equation

    International Nuclear Information System (INIS)

    Djaka, K S; Taupin, V; Berbenni, S; Fressengeas, C

    2015-01-01

    A numerical spectral approach is developed to solve in a fast, stable and accurate fashion, the quasi-linear hyperbolic transport equation governing the spatio-temporal evolution of the dislocation density tensor in the mechanics of dislocation fields. The approach relies on using the Fast Fourier Transform algorithm. Low-pass spectral filters are employed to control both the high frequency Gibbs oscillations inherent to the Fourier method and the fast-growing numerical instabilities resulting from the hyperbolic nature of the transport equation. The numerical scheme is validated by comparison with an exact solution in the 1D case corresponding to dislocation dipole annihilation. The expansion and annihilation of dislocation loops in 2D and 3D settings are also produced and compared with finite element approximations. The spectral solutions are shown to be stable, more accurate for low Courant numbers and much less computation time-consuming than the finite element technique based on an explicit Galerkin-least squares scheme. (paper)

  18. Spatiotemporal Control of Doxorubicin Delivery from “Stealth-Like” Prodrug Micelles

    Science.gov (United States)

    Kong, Li; Schneider, Gregory F.; Campbell, Frederick

    2017-01-01

    In the treatment of cancer, targeting of anticancer drugs to the tumor microenvironment is highly desirable. Not only does this imply accurate tumor targeting but also minimal drug release en route to the tumor and maximal drug release once there. Here we describe high-loading, “stealth-like” doxorubicin micelles as a pro-drug delivery system, which upon light activation, leads to burst-like doxorbicin release. Through this approach, we show precise spatiotemporal control of doxorubicin delivery to cells in vitro. PMID:28937592

  19. Numerical prediction of kinetic model for enzymatic hydrolysis of cellulose using DAE-QMOM approach

    Science.gov (United States)

    Jamil, N. M.; Wang, Q.

    2016-06-01

    Bioethanol production from lignocellulosic biomass consists of three fundamental processes; pre-treatment, enzymatic hydrolysis, and fermentation. In enzymatic hydrolysis phase, the enzymes break the cellulose chains into sugar in the form of cellobiose or glucose. A currently proposed kinetic model for enzymatic hydrolysis of cellulose that uses population balance equation (PBE) mechanism was studied. The complexity of the model due to integrodifferential equations makes it difficult to find the analytical solution. Therefore, we solved the full model of PBE numerically by using DAE-QMOM approach. The computation was carried out using MATLAB software. The numerical results were compared to the asymptotic solution developed in the author's previous paper and the results of Griggs et al. Besides confirming the findings were consistent with those references, some significant characteristics were also captured. The PBE model for enzymatic hydrolysis process can be solved using DAE-QMOM method. Also, an improved understanding of the physical insights of the model was achieved.

  20. An Efficient Numerical Approach for Solving Nonlinear Coupled Hyperbolic Partial Differential Equations with Nonlocal Conditions

    Directory of Open Access Journals (Sweden)

    A. H. Bhrawy

    2014-01-01

    Full Text Available One of the most important advantages of collocation method is the possibility of dealing with nonlinear partial differential equations (PDEs as well as PDEs with variable coefficients. A numerical solution based on a Jacobi collocation method is extended to solve nonlinear coupled hyperbolic PDEs with variable coefficients subject to initial-boundary nonlocal conservation conditions. This approach, based on Jacobi polynomials and Gauss-Lobatto quadrature integration, reduces solving the nonlinear coupled hyperbolic PDEs with variable coefficients to a system of nonlinear ordinary differential equation which is far easier to solve. In fact, we deal with initial-boundary coupled hyperbolic PDEs with variable coefficients as well as initial-nonlocal conditions. Using triangular, soliton, and exponential-triangular solutions as exact solutions, the obtained results show that the proposed numerical algorithm is efficient and very accurate.

  1. The basic approach to age-structured population dynamics models, methods and numerics

    CERN Document Server

    Iannelli, Mimmo

    2017-01-01

    This book provides an introduction to age-structured population modeling which emphasises the connection between mathematical theory and underlying biological assumptions. Through the rigorous development of the linear theory and the nonlinear theory alongside numerics, the authors explore classical equations that describe the dynamics of certain ecological systems. Modeling aspects are discussed to show how relevant problems in the fields of demography, ecology, and epidemiology can be formulated and treated within the theory. In particular, the book presents extensions of age-structured modelling to the spread of diseases and epidemics while also addressing the issue of regularity of solutions, the asymptotic behaviour of solutions, and numerical approximation. With sections on transmission models, non-autonomous models and global dynamics, this book fills a gap in the literature on theoretical population dynamics. The Basic Approach to Age-Structured Population Dynamics will appeal to graduate students an...

  2. A Novel Numerical Approach for a Nonlinear Fractional Dynamical Model of Interpersonal and Romantic Relationships

    Directory of Open Access Journals (Sweden)

    Jagdev Singh

    2017-07-01

    Full Text Available In this paper, we propose a new numerical algorithm, namely q-homotopy analysis Sumudu transform method (q-HASTM, to obtain the approximate solution for the nonlinear fractional dynamical model of interpersonal and romantic relationships. The suggested algorithm examines the dynamics of love affairs between couples. The q-HASTM is a creative combination of Sumudu transform technique, q-homotopy analysis method and homotopy polynomials that makes the calculation very easy. To compare the results obtained by using q-HASTM, we solve the same nonlinear problem by Adomian’s decomposition method (ADM. The convergence of the q-HASTM series solution for the model is adapted and controlled by auxiliary parameter ℏ and asymptotic parameter n. The numerical results are demonstrated graphically and in tabular form. The result obtained by employing the proposed scheme reveals that the approach is very accurate, effective, flexible, simple to apply and computationally very nice.

  3. Bystander or No Bystander for Gene Directed Enzyme Prodrug Therapy

    Directory of Open Access Journals (Sweden)

    Adam V. Patterson

    2009-11-01

    Full Text Available Gene directed enzyme prodrug therapy (GDEPT of cancer aims to improve the selectivity of chemotherapy by gene transfer, thus enabling target cells to convert nontoxic prodrugs to cytotoxic drugs. A zone of cell kill around gene-modified cells due to transfer of toxic metabolites, known as the bystander effect, leads to tumour regression. Here we discuss the implications of either striving for a strong bystander effect to overcome poor gene transfer, or avoiding the bystander effect to reduce potential systemic effects, with the aid of three successful GDEPT systems. This review concentrates on bystander effects and drug development with regard to these enzyme prodrug combinations, namely herpes simplex virus thymidine kinase (HSV-TK with ganciclovir (GCV, cytosine deaminase (CD from bacteria or yeast with 5-fluorocytodine (5-FC, and bacterial nitroreductase (NfsB with 5-(azaridin-1-yl-2,4-dinitrobenzamide (CB1954, and their respective derivatives.

  4. Numerical schemes for the hybrid modeling approach of gas-particle turbulent flows

    International Nuclear Information System (INIS)

    Dorogan, K.

    2012-01-01

    Hybrid Moments/PDF methods have shown to be well suitable for the description of poly-dispersed turbulent two-phase flows in non-equilibrium which are encountered in some industrial situations involving chemical reactions, combustion or sprays. They allow to obtain a fine enough physical description of the poly-dispersity, non-linear source terms and convection phenomena. However, their approximations are noised with the statistical error, which in several situations may be a source of a bias. An alternative hybrid Moments-Moments/PDF approach examined in this work consists in coupling the Moments and the PDF descriptions, within the description of the dispersed phase itself. This hybrid method could reduce the statistical error and remove the bias. However, such a coupling is not straightforward in practice and requires the development of accurate and stable numerical schemes. The approaches introduced in this work rely on the combined use of the up-winding and relaxation-type techniques. They allow to obtain stable unsteady approximations for a system of partial differential equations containing non-smooth external data which are provided by the PDF part of the model. A comparison of the results obtained using the present method with those of the 'classical' hybrid approach is presented in terms of the numerical errors for a case of a co-current gas-particle wall jet. (author)

  5. Clickable prodrugs bearing potent and hydrolytically cleavable nicotinamide phosphoribosyltransferase inhibitors

    Directory of Open Access Journals (Sweden)

    Sadrerafi K

    2018-04-01

    Full Text Available Keivan Sadrerafi, Emilia O Mason, Mark W Lee Jr Department of Chemistry, University of Missouri, Columbia, MO, USA Purpose: Our previous study indicated that carborane containing small-molecule 1-(hydroxymethyl-7-(4′-(trans-3″-(3‴-pyridylacrylamidobutyl-1,7-dicarbadodecaborane (hm-MC4-PPEA, was a potent inhibitor of nicotinamide phosphoribosyltransferase (Nampt. Nampt has been shown to be upregulated in most cancers and is a promising target for the treatment of many different types of cancers, including breast cancers. Patients and methods: To increase the selectivity of hm-MC4-PPEA toward cancer cells, three prodrugs were synthesized with different hydrolyzable linkers: ester, carbonate, and carbamate. Using click chemistry a fluorophore was attached to these prodrugs to act as a model for our conjugation strategy and to serve as an aid for prodrug stability studies. The stabilities of these drug conjugates were tested in phosphate-buffered saline (PBS at normothermia (37°C using three different pH levels, 5.5, 7.5, and 9.5, as well as in horse serum at physiological pH. The stability of each was monitored using reversed-phase HPLC equipped with both diode array and fluorescence detection. The inhibitory activity of hm-MC4-PPEA was also measured using a commercially available colorimetric assay. The biological activities of the drug conjugates as well as those of the free drug (hm-MC4-PPEA, were evaluated using the MTT assay against the human breast cancer cell lines T47D and MCF7, as well as the noncancerous, transformed, Nampt-dependent human breast epithelium cell line 184A1.Results: hm-MC4-PPEA showed to be a potent inhibitor of recombinant Nampt activity, exhibiting an IC50 concentration of 6.8 nM. The prodrugs showed great stability towards hydrolytic degradation under neutral, mildly acidic and mildly basic conditions. The carbamate prodrug also showed to be stable in rat serum. However, the carbonate and the ester prodrug

  6. A combined analytic-numeric approach for some boundary-value problems

    Directory of Open Access Journals (Sweden)

    Mustafa Turkyilmazoglu

    2016-02-01

    Full Text Available A combined analytic-numeric approach is undertaken in the present work for the solution of boundary-value problems in the finite or semi-infinite domains. Equations to be treated arise specifically from the boundary layer analysis of some two and three-dimensional flows in fluid mechanics. The purpose is to find quick but accurate enough solutions. Taylor expansions at either boundary conditions are computed which are next matched to the other asymptotic or exact boundary conditions. The technique is applied to the well-known Blasius as well as Karman flows. Solutions obtained in terms of series compare favorably with the existing ones in the literature.

  7. A Numerical-Analytical Approach to Modeling the Axial Rotation of the Earth

    Science.gov (United States)

    Markov, Yu. G.; Perepelkin, V. V.; Rykhlova, L. V.; Filippova, A. S.

    2018-04-01

    A model for the non-uniform axial rotation of the Earth is studied using a celestial-mechanical approach and numerical simulations. The application of an approximate model containing a small number of parameters to predict variations of the axial rotation velocity of the Earth over short time intervals is justified. This approximate model is obtained by averaging variable parameters that are subject to small variations due to non-stationarity of the perturbing factors. The model is verified and compared with predictions over a long time interval published by the International Earth Rotation and Reference Systems Service (IERS).

  8. Numerical Study of Natural Convection within a Wavy Enclosure Using Meshfree Approach: Effect of Corner Heating

    Directory of Open Access Journals (Sweden)

    Sonam Singh

    2014-01-01

    Full Text Available This paper presents a numerical study of natural convection within a wavy enclosure heated via corner heating. The considered enclosure is a square enclosure with left wavy side wall. The vertical wavy wall of the enclosure and both of the corner heaters are maintained at constant temperature, Tc and Th, respectively, with Th>Tc while the remaining horizontal, bottom, top and side walls are insulated. A penalty element-free Galerkin approach with reduced gauss integration scheme for penalty terms is used to solve momentum and energy equations over the complex domain with wide range of parameters, namely, Rayleigh number (Ra, Prandtl number (Pr, and range of heaters in the x- and y-direction. Numerical results are represented in terms of isotherms, streamlines, and Nusselt number. It is observed that the rate of heat transfer depends to a great extent on the Rayleigh number, Prandtl number, length of the corner heaters and the shape of the heat transfer surface. The consistent performance of the adopted numerical procedure is verified by comparison of the results obtained through the present meshless technique with those existing in the literature.

  9. Numerical algorithm for rigid body position estimation using the quaternion approach

    Science.gov (United States)

    Zigic, Miodrag; Grahovac, Nenad

    2017-11-01

    This paper deals with rigid body attitude estimation on the basis of the data obtained from an inertial measurement unit mounted on the body. The aim of this work is to present the numerical algorithm, which can be easily applied to the wide class of problems concerning rigid body positioning, arising in aerospace and marine engineering, or in increasingly popular robotic systems and unmanned aerial vehicles. Following the considerations of kinematics of rigid bodies, the relations between accelerations of different points of the body are given. A rotation matrix is formed using the quaternion approach to avoid singularities. We present numerical procedures for determination of the absolute accelerations of the center of mass and of an arbitrary point of the body expressed in the inertial reference frame, as well as its attitude. An application of the algorithm to the example of a heavy symmetrical gyroscope is presented, where input data for the numerical procedure are obtained from the solution of differential equations of motion, instead of using sensor measurements.

  10. On Thermally Interacting Multiple Boreholes with Variable Heating Strength: Comparison between Analytical and Numerical Approaches

    Directory of Open Access Journals (Sweden)

    Marc A. Rosen

    2012-08-01

    Full Text Available The temperature response in the soil surrounding multiple boreholes is evaluated analytically and numerically. The assumption of constant heat flux along the borehole wall is examined by coupling the problem to the heat transfer problem inside the borehole and presenting a model with variable heat flux along the borehole length. In the analytical approach, a line source of heat with a finite length is used to model the conduction of heat in the soil surrounding the boreholes. In the numerical method, a finite volume method in a three dimensional meshed domain is used. In order to determine the heat flux boundary condition, the analytical quasi-three-dimensional solution to the heat transfer problem of the U-tube configuration inside the borehole is used. This solution takes into account the variation in heating strength along the borehole length due to the temperature variation of the fluid running in the U-tube. Thus, critical depths at which thermal interaction occurs can be determined. Finally, in order to examine the validity of the numerical method, a comparison is made with the results of line source method.

  11. Numerical and experimental approaches to study soil transport and clogging in granular filters

    Science.gov (United States)

    Kanarska, Y.; Smith, J. J.; Ezzedine, S. M.; Lomov, I.; Glascoe, L. G.

    2012-12-01

    Failure of a dam by erosion ranks among the most serious accidents in civil engineering. The best way to prevent internal erosion is using adequate granular filters in the transition areas where important hydraulic gradients can appear. In case of cracking and erosion, if the filter is capable of retaining the eroded particles, the crack will seal and the dam safety will be ensured. Numerical modeling has proved to be a cost-effective tool for improving our understanding of physical processes. Traditionally, the consideration of flow and particle transport in porous media has focused on treating the media as continuum. Practical models typically address flow and transport based on the Darcy's law as a function of a pressure gradient and a medium-dependent permeability parameter. Additional macroscopic constitutes describe porosity, and permeability changes during the migration of a suspension through porous media. However, most of them rely on empirical correlations, which often need to be recalibrated for each application. Grain-scale modeling can be used to gain insight into scale dependence of continuum macroscale parameters. A finite element numerical solution of the Navier-Stokes equations for fluid flow together with Lagrange multiplier technique for solid particles was applied to the simulation of soil filtration in the filter layers of gravity dam. The numerical approach was validated through comparison of numerical simulations with the experimental results of base soil particle clogging in the filter layers performed at ERDC. The numerical simulation correctly predicted flow and pressure decay due to particle clogging. The base soil particle distribution was almost identical to those measured in the laboratory experiment. It is believed that the agreement between simulations and experimental data demonstrates the applicability of the proposed approach for prediction of the soil transport and clogging in embankment dams. To get more precise understanding of

  12. Topological transitions at finite temperatures: A real-time numerical approach

    International Nuclear Information System (INIS)

    Grigoriev, D.Yu.; Rubakov, V.A.; Shaposhnikov, M.E.

    1989-01-01

    We study topological transitions at finite temperatures within the (1+1)-dimensional abelian Higgs model by a numerical simulation in real time. Basic ideas of the real-time approach are presented and some peculiarities of the Metropolis technique are discussed. It is argued that the processes leading to topological transitions are of classical origin; the transitions can be observed by solving the classical field equations in real time. We show that the topological transitions actually pass via the sphaleron configuration. The transition rate as a function of temperature is found to be in good agreement with the analytical predictions. No extra suppression of the rate is observed. The conditions of applicability of our approach are discussed. The temperature interval where the low-temperature broken phase persists is estimated. (orig.)

  13. A neural approach for the numerical modeling of two-dimensional magnetic hysteresis

    International Nuclear Information System (INIS)

    Cardelli, E.; Faba, A.; Laudani, A.; Riganti Fulginei, F.; Salvini, A.

    2015-01-01

    This paper deals with a neural network approach to model magnetic hysteresis at macro-magnetic scale. Such approach to the problem seems promising in order to couple the numerical treatment of magnetic hysteresis to FEM numerical solvers of the Maxwell's equations in time domain, as in case of the non-linear dynamic analysis of electrical machines, and other similar devices, making possible a full computer simulation in a reasonable time. The neural system proposed consists of four inputs representing the magnetic field and the magnetic inductions components at each time step and it is trained by 2-d measurements performed on the magnetic material to be modeled. The magnetic induction B is assumed as entry point and the output of the neural system returns the predicted value of the field H at the same time step. A suitable partitioning of the neural system, described in the paper, makes the computing process rather fast. Validations with experimental tests and simulations for non-symmetric and minor loops are presented

  14. The synthesis of amphipathic prodrugs of 1,2-diol drugs with saccharide conjugates by high regioselective enzymatic protocol.

    Science.gov (United States)

    Quan, Jing; Chen, Zhichun; Han, Chengyou; Lin, Xianfu

    2007-02-15

    A facile, high regioselective enzymatic synthesis approach for the preparation of amphipathic prodrugs with saccharides of mephenesin and chlorphenesin was developed. Firstly, transesterification of two drugs with divinyl dicarboxylates with different carbon chain length was performed under the catalysis of Candida antarctica lipase acrylic resin and Lipozyme in anhydrous acetone at 50 degrees C, respectively. A series of lipophilic derivatives with vinyl groups of mephenesin and chlorphenesin were prepared. The influences of different organic solvents, enzyme sources, reaction time, and the acylation reagents on the synthesis of vinyl esters were investigated. And then, protease-catalyzed high regioselective acylation of D-glucose and D-mannose with vinyl esters of mephenesin and chlorphenesin gave drug-saccharide derivatives in good yields. The studies of lipophilicity and hydrolysis in vitro of prodrugs verified that drug-saccharide derivatives had amphipathic properties, and both lipophilic and amphipathic drug derivatives had obvious controlled release characteristics.

  15. Comparison of Numerical Approaches to a Steady-State Landscape Equation

    Science.gov (United States)

    Bachman, S.; Peckham, S.

    2008-12-01

    A mathematical model of an idealized fluvial landscape has been developed, in which a land surface will evolve to preserve dendritic channel networks as the surface is lowered. The physical basis for this model stems from the equations for conservation of mass for water and sediment. These equations relate the divergence of the 2D vector fields showing the unit-width discharge of water and sediment to the excess rainrate and tectonic uplift on the land surface. The 2D flow direction is taken to be opposite to the water- surface gradient vector. These notions are combined with a generalized Manning-type flow resistance formula and a generalized sediment transport law to give a closed mathematical system that can, in principle, be solved for all variables of interest: discharge of water and sediment, land surface height, vertically- averaged flow velocity, water depth, and shear stress. The hydraulic geometry equations (Leopold et. al, 1964, 1995) are used to incorporate width, depth, velocity, and slope of river channels as powers of the mean-annual river discharge. Combined, they give the unit- width discharge of the stream as a power, γ, of the water surface slope. The simplified steady-state model takes into account three components among those listed above: conservation of mass for water, flow opposite the gradient, and a slope-discharge exponent γ = -1 to reflect mature drainage networks. The mathematical representation of this model appears as a second-order hyperbolic partial differential equation (PDE) where the diffusivity is inversely proportional to the square of the local surface slope. The highly nonlinear nature of this PDE has made it very difficult to solve both analytically and numerically. We present simplistic analytic solutions to this equation which are used to test the validity of the numerical algorithms. We also present three such numerical approaches which have been used in solving the differential equation. The first is based on a

  16. Ion diode simulation with a finite-volume PIC approach for the numerical solution of the Maxwell-Lorentz system

    Energy Technology Data Exchange (ETDEWEB)

    Munz, C D; Schneider, R; Stein, E; Voss, U [Forschungszentrum Karlsruhe (Germany). Institut fuer Neutronenphysik und Reaktortechnik; Westermann, T [FH Karlsruhe (Germany). Fachbereich Naturwissenschaften; Krauss, M [Forschungszentrum Karlsruhe (Germany). Hauptabteilung Informations- und Kommunikationstechik

    1997-12-31

    The numerical concept realized in the the Karlsruhe Diode Code KADI2D is briefly reviewed. Several new aspects concerning the Maxwell field solver based on high resolution finite-volume methods are presented. A new approach maintaining charge conservation numerically for the Maxwell-Lorentz equations is shortly summarized. (author). 2 figs., 12 refs.

  17. Ion diode simulation with a finite-volume PIC approach for the numerical solution of the Maxwell-Lorentz system

    International Nuclear Information System (INIS)

    Munz, C.D.; Schneider, R.; Stein, E.; Voss, U.; Westermann, T.; Krauss, M.

    1996-01-01

    The numerical concept realized in the the Karlsruhe Diode Code KADI2D is briefly reviewed. Several new aspects concerning the Maxwell field solver based on high resolution finite-volume methods are presented. A new approach maintaining charge conservation numerically for the Maxwell-Lorentz equations is shortly summarized. (author). 2 figs., 12 refs

  18. PRODRUGS OF NON- STEROID ANTI - INFLAMMATORY AGENTS (NSAIDS)

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to novel depot formulations (prodrugs) comprising an immobility promoting unit linked via an ester to an active pharmaceutical ingredient, i.a. common NSAIDs. The novel depot formulations are suitable for intra-articular injections and are soluble at slightly acidic p...

  19. Amino Acid Ester Prodrugs of Nucleoside and Nucleotide Antivirals

    Czech Academy of Sciences Publication Activity Database

    Krečmerová, Marcela

    2017-01-01

    Roč. 17, č. 10 (2017), s. 818-833 ISSN 1389-5575 Grant - others:AV ČR(CZ) M200551201 Institutional support: RVO:61388963 Keywords : acyclic nucleoside analogues * antiherpetics * antiretrovirals * cidofovir * peptidomimetics * prodrugs Subject RIV: CC - Organic Chemistry OBOR OECD: Organic chemistry Impact factor: 2.661, year: 2016

  20. Antiviral acyclic nucleoside phosphonates: New structures and prodrugs

    Czech Academy of Sciences Publication Activity Database

    Krečmerová, Marcela; Tichý, Tomáš; Pomeisl, Karel; Andrei, G.; Balzarini, J.; Snoeck, R.

    2016-01-01

    Roč. 1, č. 2 (2016), s. 37 [PharmaMed-2016. International Conference on Medicinal and Pharmaceutical Chemistry . 05.12.2016-07.12.2016, Dubai] R&D Projects: GA ČR(CZ) GA14-00522S Institutional support: RVO:61388963 Keywords : acyclic nucleoside phosphonates * prodrugs * antivirals * 5-azacytosine Subject RIV: CC - Organic Chemistry

  1. Novel Polymeric Prodrugs of Valproic Acid as Anti- Epilepsy Drugs ...

    African Journals Online (AJOL)

    The release of VPA from polymeric prodrugs was studied using cellophane membrane dialysis bags containing aqueous buffer solutions (pH 1, 7 and 10) at 37 oC. The quantity of released drug was detected by ultraviolet (UV) spectroscopy. Results: 1H-NMR and elemental analyses data for calculating mole composition of ...

  2. Degradation kinetics of metronidazole and its mutual prodrug with ...

    African Journals Online (AJOL)

    Dr Renu Chadha

    degradation of the drug and prodrug as a function of concentration, pH and temperature. In terms of enthalpy of ... Keywords: Calorimetry, stability studies, degradation kinetics, ciprofloxacin, metronidazole. ... action of ciprofloxacin to form a broad spectrum ...... Stability testing of pharmaceutical by isothermal heat conduction.

  3. Reinforced concrete structures loaded by snow avalanches : numerical and experimental approaches.

    Science.gov (United States)

    Ousset, I.; Bertrand, D.; Brun, M.; Limam, A.; Naaim, M.

    2012-04-01

    Today, due to the extension of occupied areas in mountainous regions, new strategies for risk mitigation have to be developed. In the framework of risk analysis, these latter have to take into account not only the natural hazard description but also the physical vulnerability of the exposed structures. From a civil engineering point of view, the dynamic behavior of column or portico was widely investigated especially in the case of reinforced concrete and steel. However, it is not the case of reinforced concrete walls for which only the in-plan dynamic behavior (shear behavior) has been studied in detail in the field of earthquake engineering. Therefore, the aim of this project is to study the behavior of reinforced concrete civil engineering structures submitted to out-of-plan dynamic loadings coming from snow avalanche interaction. Numerical simulations in 2D or 3D by the finite element method (FEM) are presented. The approach allows solving mechanical problems in dynamic condition involving none linearities (especially none linear materials). Thus, the structure mechanical response can be explored in controlled conditions. First, a reinforced concrete wall with a L-like shape is considered. The structure is supposed to represent a French defense structure dedicated to protect people against snow avalanches. Experimental pushover tests have been performed on a physical model. The experimental tests consisted to apply a uniform distribution of pressure until the total collapse of the wall. A 2D numerical model has been developed to simulate the mechanical response of the structure under quasi-static loading. Numerical simulations have been compared to experimental datas and results gave a better understanding of the failure mode of the wall. Moreover, the influence of several parameters (geometry and the mechanical properties) is also presented. Secondly, punching shear experimental tests have also been carried out. Reinforced concrete slabs simply supported have

  4. Numerical Prediction of CCV in a PFI Engine using a Parallel LES Approach

    Energy Technology Data Exchange (ETDEWEB)

    Ameen, Muhsin M; Mirzaeian, Mohsen; Millo, Federico; Som, Sibendu

    2017-10-15

    Cycle-to-cycle variability (CCV) is detrimental to IC engine operation and can lead to partial burn, misfire, and knock. Predicting CCV numerically is extremely challenging due to two key reasons. Firstly, high-fidelity methods such as large eddy simulation (LES) are required to accurately resolve the incylinder turbulent flowfield both spatially and temporally. Secondly, CCV is experienced over long timescales and hence the simulations need to be performed for hundreds of consecutive cycles. Ameen et al. (Int. J. Eng. Res., 2017) developed a parallel perturbation model (PPM) approach to dissociate this long time-scale problem into several shorter timescale problems. The strategy is to perform multiple single-cycle simulations in parallel by effectively perturbing the initial velocity field based on the intensity of the in-cylinder turbulence. This strategy was demonstrated for motored engine and it was shown that the mean and variance of the in-cylinder flowfield was captured reasonably well by this approach. In the present study, this PPM approach is extended to simulate the CCV in a fired port-fuel injected (PFI) SI engine. Two operating conditions are considered – a medium CCV operating case corresponding to 2500 rpm and 16 bar BMEP and a low CCV case corresponding to 4000 rpm and 12 bar BMEP. The predictions from this approach are also shown to be similar to the consecutive LES cycles. Both the consecutive and PPM LES cycles are observed to under-predict the variability in the early stage of combustion. The parallel approach slightly underpredicts the cyclic variability at all stages of combustion as compared to the consecutive LES cycles. However, it is shown that the parallel approach is able to predict the coefficient of variation (COV) of the in-cylinder pressure and burn rate related parameters with sufficient accuracy, and is also able to predict the qualitative trends in CCV with changing operating conditions. The convergence of the statistics

  5. 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.

  6. Amphipathic dextran-doxorubicin prodrug micelles for solid tumor therapy.

    Science.gov (United States)

    Jin, Rong; Guo, Xuelian; Dong, Lingli; Xie, Enyuan; Cao, Aoneng

    2017-10-01

    A group of micelles self-assembled from deoxycholic acid-doxorubicin-conjugated dextran (denoted as Dex-DCA-DOX) prodrugs were designed and prepared for pH-triggered drug release and cancer chemotherapy. These prodrugs could be successfully produced by chemically coupling hydrophobic deoxycholic acid (DCA) to dextran hydrazine (denoted as Dex-NHNH 2 ) and hydrazone linker formation between doxorubicin (DOX) and Dex-NHNH 2 . These Dex-DCA-DOX prodrugs self-assembled to form micelles under physiological conditions with varied particle sizes depending on molecular weight of dextran, degree of substitution (DS) of DCA and DOX. After optimization, Dex10k-DCA9-DOX5.5 conjugate comprising dextran of 10kDa, DCA of DS 9 and DOX loading content of 5.5wt%, formed the micelles with the smallest size (110nm). These prodrug micelles could slowly liberate DOX under physiological conditions but efficiently released the drug at an acidified endosomal pH by the hydrolysis of acid-labile hydrazone linker. In vitro cytotoxicity experiment indicated that Dex10k-DCA9-DOX5.5 micelles exerted marked antitumor activity against MCF-7 and SKOV-3 cancer cells. Besides, intravenous administration of the micelles afforded growth inhibition of SKOV-3 tumor bearing in nude mice at a dosage of 2.5mg per kg with anti-cancer efficacy comparable to free DOX-chemotherapy but low systemic toxicity. This study highlights the feasibility of bio-safe and efficient dextran-based prodrug micelles designed for cancer chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. A different approach to estimate nonlinear regression model using numerical methods

    Science.gov (United States)

    Mahaboob, B.; Venkateswarlu, B.; Mokeshrayalu, G.; Balasiddamuni, P.

    2017-11-01

    This research paper concerns with the computational methods namely the Gauss-Newton method, Gradient algorithm methods (Newton-Raphson method, Steepest Descent or Steepest Ascent algorithm method, the Method of Scoring, the Method of Quadratic Hill-Climbing) based on numerical analysis to estimate parameters of nonlinear regression model in a very different way. Principles of matrix calculus have been used to discuss the Gradient-Algorithm methods. Yonathan Bard [1] discussed a comparison of gradient methods for the solution of nonlinear parameter estimation problems. However this article discusses an analytical approach to the gradient algorithm methods in a different way. This paper describes a new iterative technique namely Gauss-Newton method which differs from the iterative technique proposed by Gorden K. Smyth [2]. Hans Georg Bock et.al [10] proposed numerical methods for parameter estimation in DAE’s (Differential algebraic equation). Isabel Reis Dos Santos et al [11], Introduced weighted least squares procedure for estimating the unknown parameters of a nonlinear regression metamodel. For large-scale non smooth convex minimization the Hager and Zhang (HZ) conjugate gradient Method and the modified HZ (MHZ) method were presented by Gonglin Yuan et al [12].

  8. Experimental and numerical approaches to studying hot cracking in stainless steel welds

    International Nuclear Information System (INIS)

    Le, Minh

    2014-01-01

    This work concerns experimental and numerical approaches to studying hot cracking in welds in stainless steel. Metallurgical weldability of two filler products used for the welding of an AISI-316L(N) austenitic stainless steel grade is evaluated. These filler metals are distinguished by their solidification microstructures: austeno-ferritic for the 19Cr-12Ni-2Mo grade and austenitic for the 19-15H Thermanit grade. The study of weldability concerns the assessment of the susceptibility to hot cracking of these three alloys, the proposition of a hot cracking criterion, and the evaluation of its transferability to structure-scale tests. Hot cracks are material separations occurring at high temperatures along the grain boundaries (dendrite boundaries), when the level of strain and the strain rate exceed a certain level. The hot cracks studied are formed during solidification from the liquid phase of weld metals. The bibliography study brings to the fore the complexity of initiation and propagation mechanisms of these material separations. Three types of tests are studied in this work: hot cracking tests, such as trapezoidal and Varestraint tests, allowing to initiate the phenomenon in controlled experimental conditions, and tests on the Gleeble thermomechanical simulator for thermomechanical (materials behavior laws, fracture properties) and metallurgical (brittle temperature range (BTR), evolution of delta ferrite) characterizations of the alloys. All these tests on the three materials were analyzed via numerical modeling and simulations implemented in the Cast3M finite element code in order to bring out a thermomechanical hot cracking criterion. (author) [fr

  9. A numerical integration approach suitable for simulating PWR dynamics using a microcomputer system

    International Nuclear Information System (INIS)

    Zhiwei, L.; Kerlin, T.W.

    1983-01-01

    It is attractive to use microcomputer systems to simulate nuclear power plant dynamics for the purpose of teaching and/or control system design. An analysis and a comparison of feasibility of existing numerical integration methods have been made. The criteria for choosing the integration step using various numerical integration methods including the matrix exponential method are derived. In order to speed up the simulation, an approach is presented using the Newton recursion calculus which can avoid convergence limitations in choosing the integration step size. The accuracy consideration will dominate the integration step limited. The advantages of this method have been demonstrated through a case study using CBM model 8032 microcomputer to simulate a reduced order linear PWR model under various perturbations. It has been proven theoretically and practically that the Runge-Kutta method and Adams-Moulton method are not feasible. The matrix exponential method is good at accuracy and fairly good at speed. The Newton recursion method can save 3/4 to 4/5 time compared to the matrix exponential method with reasonable accuracy. Vertical Barhis method can be expanded to deal with nonlinear nuclear power plant models and higher order models as well

  10. Computational modeling and in-vitro/in-silico correlation of phospholipid-based prodrugs for targeted drug delivery in inflammatory bowel disease

    Science.gov (United States)

    Dahan, Arik; Markovic, Milica; Keinan, Shahar; Kurnikov, Igor; Aponick, Aaron; Zimmermann, Ellen M.; Ben-Shabat, Shimon

    2017-11-01

    Targeting drugs to the inflamed intestinal tissue(s) represents a major advancement in the treatment of inflammatory bowel disease (IBD). In this work we present a powerful in-silico modeling approach to guide the molecular design of novel prodrugs targeting the enzyme PLA2, which is overexpressed in the inflamed tissues of IBD patients. The prodrug consists of the drug moiety bound to the sn-2 position of phospholipid (PL) through a carbonic linker, aiming to allow PLA2 to release the free drug. The linker length dictates the affinity of the PL-drug conjugate to PLA2, and the optimal linker will enable maximal PLA2-mediated activation. Thermodynamic integration and Weighted Histogram Analysis Method (WHAM)/Umbrella Sampling method were used to compute the changes in PLA2 transition state binding free energy of the prodrug molecule (ΔΔGtr) associated with decreasing/increasing linker length. The simulations revealed that 6-carbons linker is the optimal one, whereas shorter or longer linkers resulted in decreased PLA2-mediated activation. These in-silico results were shown to be in excellent correlation with experimental in-vitro data. Overall, this modern computational approach enables optimization of the molecular design of novel prodrugs, which may allow targeting the free drug specifically to the diseased intestinal tissue of IBD patients.

  11. The brush model - a new approach to numerical modeling of matrix diffusion in fractured clay stone

    International Nuclear Information System (INIS)

    Lege, T.; Shao, H.

    1998-01-01

    A special approach for numerical modeling of contaminant transport in fractured clay stone is presented. The rock matrix and the fractures are simulated with individual formulations for FE grids and transport, coupled into a single model. The capacity of the rock matrix to take up contaminants is taken into consideration with a discrete simulation of matrix diffusion. Thus, the natural process of retardation due to matrix diffusion can be better simulated than by a standard introduction of an empirical parameter into the transport equation. Transport in groundwater in fractured clay stone can be simulated using a model called a 'brush model'. The 'brush handle' is discretized by 2-D finite elements. Advective-dispersive transport in groundwater in the fractures is assumed. The contaminant diffuses into 1D finite elements perpendicular to the fractures, i.e., the 'bristles of the brush'. The conclusion is drawn that matrix diffusion is an important property of fractured clay stone for contaminant retardation. (author)

  12. A probabilistic approach for debris impact risk with numerical simulations of debris behaviors

    International Nuclear Information System (INIS)

    Kihara, Naoto; Matsuyama, Masafumi; Fujii, Naoki

    2013-01-01

    We propose a probabilistic approach for evaluating the impact risk of tsunami debris through Monte Carlo simulations with a combined system comprising a depth-averaged two-dimensional shallow water model and a discrete element model customized to simulate the motions of floating objects such as vessels. In the proposed method, first, probabilistic tsunami hazard analysis is carried out, and the exceedance probability of tsunami height and numerous tsunami time series for various hazard levels on the offshore side of a target site are estimated. Second, a characteristic tsunami time series for each hazard level is created by cluster analysis. Third, using the Monte Carlo simulation model the debris impact probability with the buildings of interest and the exceedance probability of debris impact speed are evaluated. (author)

  13. Numerical studies of rotational core collapse in axisymmetry using the conformally flat metric approach

    International Nuclear Information System (INIS)

    Dimmelmeier, H.; Font, J.A.; Mueller, E.

    2001-01-01

    The numerical simulation of hydrodynamic processes in general relativity is a highly complex problem. In order to reduce the complexity of the gravitational field equations, Wilson and coworkers have proposed an approximation scheme, where the 3-metric γ ij is chosen to be conformally flat. In this approximation the Einstein equations reduce to a set of 5 coupled elliptic equations. In this paper we present an axisymmetric general relativistic hydrodynamic code which utilizes this approach together with high-resolution shock-capturing schemes to solve the hydrodynamic equations. We report on tests and preliminary applications of the code to rotating neutron stars and supernova core collapse in axisymmetry. The code promises good applicability to handle a variety of relativistic astrophysical situations, and is prepared to provide information about gravitational radiation from rotating gravitational collapse. (author)

  14. Operating environment threats influence on the maritime ferry technical system safety – the numerical approach

    Directory of Open Access Journals (Sweden)

    Kuligowska Ewa

    2017-06-01

    Full Text Available The material given in this paper delivers the procedure for numerical approach that allows finding the main practically important safety characteristics of the complex technical systems at the variable operation conditions including operating environment threats. The obtained results are applied to the safety evaluation of the maritime ferry technical system. It is assumed that the conditional safety functions are different at various operation states and have the exponential forms. Using the procedure and the program written in Mathematica, the considered maritime ferry technical system main characteristics including: the conditional and the unconditional expected values and standard deviations of the system lifetimes, the unconditional safety function and the risk function are determined.

  15. Three dimensional, numerical analysis of an elasto hydrodynamic lubrication using fluid structure interaction (FSI) approach

    Science.gov (United States)

    Hanoca, P.; Ramakrishna, H. V.

    2018-03-01

    This work is related to develop a methodology to model and simulate the TEHD using the sequential application of CFD and CSD. The FSI analyses are carried out using ANSYS Workbench. In this analysis steady state, 3D Navier-Stoke equations along with energy equation are solved. Liquid properties are introduced where the viscosity and density are the function of pressure and temperature. The cavitation phenomenon is adopted in the analysis. Numerical analysis has been carried at different speeds and surfaces temperatures. During the analysis, it was found that as speed increases, hydrodynamic pressures will also increases. The pressure profile obtained from the Roelands equation is more sensitive to the temperature as compared to the Barus equation. The stress distributions specify the significant positions in the bearing structure. The developed method is capable of giving latest approaching into the physics of elasto hydrodynamic lubrication.

  16. A Numerical Approach to the Dynamic Response of the Deployment System during a Circular Cylinder Crossing through the Wave Zone

    Directory of Open Access Journals (Sweden)

    Xiaozhou Hu

    2017-01-01

    Full Text Available The dynamic response of the deployment system while deploying a circular cylinder crossing wave surface and the following submerging process are investigated numerically. The present numerical approach is based on the combination of solution methods of cable dynamics and computational fluid dynamics (CFD. For the implementation of the numerical approach, a cosimulation platform based on a CFD code and MATLAB is developed to study the fluid-solid interaction problem in the process. To generate regular waves, a numerical wave tank is built based on a piston-type wave generation method and a wave damping method applying porous media. Numerical simulations are performed based on the cosimulation platform. The sensitivities of cable tension, velocity, and acceleration of deployed body to different input parameters are investigated, including phase angles, wave heights, and periods of regular waves and deploying velocities, and the effects of those input parameters on dynamic responses of the deployment system are also discussed.

  17. Numerical probabilistic analysis for slope stability in fractured rock masses using DFN-DEM approach

    Directory of Open Access Journals (Sweden)

    Alireza Baghbanan

    2017-06-01

    Full Text Available Due to existence of uncertainties in input geometrical properties of fractures, there is not any unique solution for assessing the stability of slopes in jointed rock masses. Therefore, the necessity of applying probabilistic analysis in these cases is inevitable. In this study a probabilistic analysis procedure together with relevant algorithms are developed using Discrete Fracture Network-Distinct Element Method (DFN-DEM approach. In the right abutment of Karun 4 dam and downstream of the dam body, five joint sets and one major joint have been identified. According to the geometrical properties of fractures in Karun river valley, instability situations are probable in this abutment. In order to evaluate the stability of the rock slope, different combinations of joint set geometrical parameters are selected, and a series of numerical DEM simulations are performed on generated and validated DFN models in DFN-DEM approach to measure minimum required support patterns in dry and saturated conditions. Results indicate that the distribution of required bolt length is well fitted with a lognormal distribution in both circumstances. In dry conditions, the calculated mean value is 1125.3 m, and more than 80 percent of models need only 1614.99 m of bolts which is a bolt pattern with 2 m spacing and 12 m length. However, as for the slopes with saturated condition, the calculated mean value is 1821.8 m, and more than 80 percent of models need only 2653.49 m of bolts which is equivalent to a bolt pattern with 15 m length and 1.5 m spacing. Comparison between obtained results with numerical and empirical method show that investigation of a slope stability with different DFN realizations which conducted in different block patterns is more efficient than the empirical methods.

  18. Numerical approach of multi-field two-phase flow models in the OVAP code

    International Nuclear Information System (INIS)

    Anela Kumbaro

    2005-01-01

    Full text of publication follows: A significant progress has been made in modeling the complexity of vapor-liquid two-phase flow. Different three-dimensional models exist in order to simulate the evolution of parameters which characterize a two-phase model. These models can be classified into various groups depending on the inter-field coupling. A hierarchy of increasing physical complexity can be defined. The simplest group corresponds to the homogeneous mixture models where no interactions are taken into account. Another group is constituted by the two-fluid models employing physically important interfacial forces between two-phases, liquid, and water. The last group is multi-field modeling where inter-field couplings can be taken into account at different degrees, such as the MUltiple Size Group modeling [2], the consideration of separate equations for the transport and generation of mass and momentum for each field under the assumption of the same energy for all the fields of the same phase, and a full multi-field two-phase model [1]. The numerical approach of the general three-dimensional two-phase flow is by complexity of the phenomena a very challenging task; the ideal numerical method should be at the same time simple in order to apply to any model, from equilibrium to multi-field model and conservative in order to respect the fundamental conservation physical laws. The approximate Riemann solvers have the good properties of conservation of mass, momentum and energy balance and have been extended successfully to two-fluid models [3]- [5]. But, the up-winding of the flux is based on the Eigen-decomposition of the two-phase flow model and the computation of the Eigen-structure of a multi-field model can be a high cost procedure. Our contribution will present a short review of the above two-phase models, and show numerical results obtained for some of them with an approximate Riemann solver and with lower-complexity alternative numerical methods that do not

  19. Discovery of an L-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100.

    Science.gov (United States)

    Kim, Se-Ho; Tangallapally, Rajendra; Kim, In Chul; Trovato, Richard; Parker, Daniel; Patton, J Scott; Reeves, Leslie; Bradford, Chad; Wettstein, Daniel; Baichwal, Vijay; Papac, Damon; Bajji, Ashok; Carlson, Robert; Yager, Kraig M

    2015-11-15

    Various types of Hsp90 inhibitors have been and continue to undergo clinical investigation. One development candidate is the purine-based, synthetic Hsp90 inhibitor 1 (MPC-3100), which successfully completed a phase I clinical study. However, further clinical development of 1 was hindered by poor solubility and consequent formulation issues and promoted development of a more water soluble prodrug. Towards this end, numerous pro-moieties were explored in vitro and in vivo. These studies resulted in identification of L-alanine ester mesylate, 2i (MPC-0767), which exhibited improved aqueous solubility, adequate chemical stability, and rapid bioconversion without the need for solubilizing excipients. Based on improved physical characteristics and favorable PK and PD profiles, 2i mesylate was selected for further development. A convergent, scalable, chromatography-free synthesis for 2i mesylate was developed to support further clinical evaluation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Development of a Numerical Approach to Simulate Compressed Air Energy Storage Subjected to Cyclic Internal Pressure

    Directory of Open Access Journals (Sweden)

    Song-Hun Chong

    2017-10-01

    Full Text Available This paper analyzes the long-term response of unlined energy storage located at shallow depth to improve the distance between a wind farm and storage. The numerical approach follows the hybrid scheme that combined a mechanical constitutive model to extract stress and strains at the first cycle and polynomial-type strain accumulation functions to track the progressive plastic deformation. In particular, the strain function includes the fundamental features that requires simulating the long-term response of geomaterials: volumetric strain (terminal void ratio and shear strain (shakedown and ratcheting, the strain accumulation rate, and stress obliquity. The model is tested with a triaxial strain boundary condition under different stress obliquities. The unlined storage subjected to cyclic internal stress is simulated with different storage geometries and stress amplitudes that play a crucial role in estimating the long-term mechanical stability of underground storage. The simulations present the evolution of ground surface, yet their incremental rate approaches towards a terminal void ratio. With regular and smooth displacement fields for the large number of cycles, the inflection point is estimated with the previous surface settlement model.

  1. Dimensionless Numerical Approaches for the Performance Prediction of Marine Waterjet Propulsion Units

    Directory of Open Access Journals (Sweden)

    Marco Altosole

    2012-01-01

    Full Text Available One of the key issues at early design stage of a high-speed craft is the selection and the performance prediction of the propulsion system because at this stage only few information about the vessel are available. The objective of this work is precisely to provide the designer, in the case of waterjet propelled craft, with a simple and reliable calculation tool, able to predict the waterjet working points in design and off-design conditions, allowing to investigate several propulsive options during the ship design process. In the paper two original dimensionless numerical procedures, one referred to jet units for naval applications and the other more suitable for planing boats, are presented. The first procedure is based on a generalized performance map for mixed flow pumps, derived from the analysis of several waterjet pumps by applying similitude principles of the hydraulic machines. The second approach, validated by some comparisons with current waterjet installations, is based on a complete physical approach, from which a set of non-dimensional waterjet characteristics has been drawn by the authors. The presented application examples show the validity and the degree of accuracy of the proposed methodologies for the performance evaluation of waterjet propulsion systems.

  2. Towards a category theory approach to analogy: Analyzing re-representation and acquisition of numerical knowledge.

    Directory of Open Access Journals (Sweden)

    Jairo A Navarrete

    2017-08-01

    Full Text Available Category Theory, a branch of mathematics, has shown promise as a modeling framework for higher-level cognition. We introduce an algebraic model for analogy that uses the language of category theory to explore analogy-related cognitive phenomena. To illustrate the potential of this approach, we use this model to explore three objects of study in cognitive literature. First, (a we use commutative diagrams to analyze an effect of playing particular educational board games on the learning of numbers. Second, (b we employ a notion called coequalizer as a formal model of re-representation that explains a property of computational models of analogy called "flexibility" whereby non-similar representational elements are considered matches and placed in structural correspondence. Finally, (c we build a formal learning model which shows that re-representation, language processing and analogy making can explain the acquisition of knowledge of rational numbers. These objects of study provide a picture of acquisition of numerical knowledge that is compatible with empirical evidence and offers insights on possible connections between notions such as relational knowledge, analogy, learning, conceptual knowledge, re-representation and procedural knowledge. This suggests that the approach presented here facilitates mathematical modeling of cognition and provides novel ways to think about analogy-related cognitive phenomena.

  3. Multi-scale approach in numerical reservoir simulation; Uma abordagem multiescala na simulacao numerica de reservatorios

    Energy Technology Data Exchange (ETDEWEB)

    Guedes, Solange da Silva

    1998-07-01

    Advances in petroleum reservoir descriptions have provided an amount of data that can not be handled directly during numerical simulations. This detailed geological information must be incorporated into a coarser model during multiphase fluid flow simulations by means of some upscaling technique. the most used approach is the pseudo relative permeabilities and the more widely used is the Kyte and Berry method (1975). In this work, it is proposed a multi-scale computational model for multiphase flow that implicitly treats the upscaling without using pseudo functions. By solving a sequence of local problems on subdomains of the refined scale it is possible to achieve results with a coarser grid without expensive computations of a fine grid model. The main advantage of this new procedure is to treat the upscaling step implicitly in the solution process, overcoming some practical difficulties related the use of traditional pseudo functions. results of bidimensional two phase flow simulations considering homogeneous porous media are presented. Some examples compare the results of this approach and the commercial upscaling program PSEUDO, a module of the reservoir simulation software ECLIPSE. (author)

  4. Towards a category theory approach to analogy: Analyzing re-representation and acquisition of numerical knowledge.

    Science.gov (United States)

    Navarrete, Jairo A; Dartnell, Pablo

    2017-08-01

    Category Theory, a branch of mathematics, has shown promise as a modeling framework for higher-level cognition. We introduce an algebraic model for analogy that uses the language of category theory to explore analogy-related cognitive phenomena. To illustrate the potential of this approach, we use this model to explore three objects of study in cognitive literature. First, (a) we use commutative diagrams to analyze an effect of playing particular educational board games on the learning of numbers. Second, (b) we employ a notion called coequalizer as a formal model of re-representation that explains a property of computational models of analogy called "flexibility" whereby non-similar representational elements are considered matches and placed in structural correspondence. Finally, (c) we build a formal learning model which shows that re-representation, language processing and analogy making can explain the acquisition of knowledge of rational numbers. These objects of study provide a picture of acquisition of numerical knowledge that is compatible with empirical evidence and offers insights on possible connections between notions such as relational knowledge, analogy, learning, conceptual knowledge, re-representation and procedural knowledge. This suggests that the approach presented here facilitates mathematical modeling of cognition and provides novel ways to think about analogy-related cognitive phenomena.

  5. Science-Based Approach for Advancing Marine and Hydrokinetic Energy: Integrating Numerical Simulations with Experiments

    Science.gov (United States)

    Sotiropoulos, F.; Kang, S.; Chamorro, L. P.; Hill, C.

    2011-12-01

    The field of MHK energy is still in its infancy lagging approximately a decade or more behind the technology and development progress made in wind energy engineering. Marine environments are characterized by complex topography and three-dimensional (3D) turbulent flows, which can greatly affect the performance and structural integrity of MHK devices and impact the Levelized Cost of Energy (LCoE). Since the deployment of multi-turbine arrays is envisioned for field applications, turbine-to-turbine interactions and turbine-bathymetry interactions need to be understood and properly modeled so that MHK arrays can be optimized on a site specific basis. Furthermore, turbulence induced by MHK turbines alters and interacts with the nearby ecosystem and could potentially impact aquatic habitats. Increased turbulence in the wake of MHK devices can also change the shear stress imposed on the bed ultimately affecting the sediment transport and suspension processes in the wake of these structures. Such effects, however, remain today largely unexplored. In this work a science-based approach integrating state-of-the-art experimentation with high-resolution computational fluid dynamics is proposed as a powerful strategy for optimizing the performance of MHK devices and assessing environmental impacts. A novel numerical framework is developed for carrying out Large-Eddy Simulation (LES) in arbitrarily complex domains with embedded MHK devices. The model is able to resolve the geometrical complexity of real-life MHK devices using the Curvilinear Immersed Boundary (CURVIB) method along with a wall model for handling the flow near solid surfaces. Calculations are carried out for an axial flow hydrokinetic turbine mounted on the bed of rectangular open channel on a grid with nearly 200 million grid nodes. The approach flow corresponds to fully developed turbulent open channel flow and is obtained from a separate LES calculation. The specific case corresponds to that studied

  6. Numerical relativity

    International Nuclear Information System (INIS)

    Piran, T.

    1982-01-01

    There are many recent developments in numerical relativity, but there remain important unsolved theoretical and practical problems. The author reviews existing numerical approaches to solution of the exact Einstein equations. A framework for classification and comparison of different numerical schemes is presented. Recent numerical codes are compared using this framework. The discussion focuses on new developments and on currently open questions, excluding a review of numerical techniques. (Auth.)

  7. pH- and NIR Light-Responsive Polymeric Prodrug Micelles for Hyperthermia-Assisted Site-Specific Chemotherapy to Reverse Drug Resistance in Cancer Treatment.

    Science.gov (United States)

    Li, Zuhong; Wang, Haibo; Chen, Yangjun; Wang, Yin; Li, Huan; Han, Haijie; Chen, Tingting; Jin, Qiao; Ji, Jian

    2016-05-01

    Despite the exciting advances in cancer chemotherapy over past decades, drug resistance in cancer treatment remains one of the primary reasons for therapeutic failure. IR-780 loaded pH-responsive polymeric prodrug micelles with near infrared (NIR) photothermal effect are developed to circumvent the drug resistance in cancer treatment. The polymeric prodrug micelles are stable in physiological environment, while exhibit fast doxorubicin (DOX) release in acidic condition and significant temperature elevation under NIR laser irradiation. Phosphorylcholine-based biomimetic micellar shell and acid-sensitive drug conjugation endow them with prolonged circulation time and reduced premature drug release during circulation to conduct tumor site-specific chemotherapy. The polymeric prodrug micelles combined with NIR laser irradiation could significantly enhance intracellular DOX accumulation and synergistically induce the cell apoptosis in DOX-resistant MCF-7/ADR cells. Meanwhile, the tumor site-specific chemotherapy combined with hyperthermia effect induces significant inhibition of MCF-7/ADR tumor growth in tumor-bearing mice. These results demonstrate that the well-designed IR-780 loaded polymeric prodrug micelles for hyperthermia-assisted site-specific chemotherapy present an effective approach to reverse drug resistance. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. PREFACE: The Second International Conference on Inverse Problems: Recent Theoretical Developments and Numerical Approaches

    Science.gov (United States)

    Cheng, Jin; Hon, Yiu-Chung; Seo, Jin Keun; Yamamoto, Masahiro

    2005-01-01

    The Second International Conference on Inverse Problems: Recent Theoretical Developments and Numerical Approaches was held at Fudan University, Shanghai from 16-21 June 2004. The first conference in this series was held at the City University of Hong Kong in January 2002 and it was agreed to hold the conference once every two years in a Pan-Pacific Asian country. The next conference is scheduled to be held at Hokkaido University, Sapporo, Japan in July 2006. The purpose of this series of biennial conferences is to establish and develop constant international collaboration, especially among the Pan-Pacific Asian countries. In recent decades, interest in inverse problems has been flourishing all over the globe because of both the theoretical interest and practical requirements. In particular, in Asian countries, one is witnessing remarkable new trends of research in inverse problems as well as the participation of many young talents. Considering these trends, the second conference was organized with the chairperson Professor Li Tat-tsien (Fudan University), in order to provide forums for developing research cooperation and to promote activities in the field of inverse problems. Because solutions to inverse problems are needed in various applied fields, we entertained a total of 92 participants at the second conference and arranged various talks which ranged from mathematical analyses to solutions of concrete inverse problems in the real world. This volume contains 18 selected papers, all of which have undergone peer review. The 18 papers are classified as follows: Surveys: four papers give reviews of specific inverse problems. Theoretical aspects: six papers investigate the uniqueness, stability, and reconstruction schemes. Numerical methods: four papers devise new numerical methods and their applications to inverse problems. Solutions to applied inverse problems: four papers discuss concrete inverse problems such as scattering problems and inverse problems in

  9. New numerical approaches for modeling thermochemical convection in a compositionally stratified fluid

    Science.gov (United States)

    Puckett, Elbridge Gerry; Turcotte, Donald L.; He, Ying; Lokavarapu, Harsha; Robey, Jonathan M.; Kellogg, Louise H.

    2018-03-01

    Geochemical observations of mantle-derived rocks favor a nearly homogeneous upper mantle, the source of mid-ocean ridge basalts (MORB), and heterogeneous lower mantle regions. Plumes that generate ocean island basalts are thought to sample the lower mantle regions and exhibit more heterogeneity than MORB. These regions have been associated with lower mantle structures known as large low shear velocity provinces (LLSVPS) below Africa and the South Pacific. The isolation of these regions is attributed to compositional differences and density stratification that, consequently, have been the subject of computational and laboratory modeling designed to determine the parameter regime in which layering is stable and understanding how layering evolves. Mathematical models of persistent compositional interfaces in the Earth's mantle may be inherently unstable, at least in some regions of the parameter space relevant to the mantle. Computing approximations to solutions of such problems presents severe challenges, even to state-of-the-art numerical methods. Some numerical algorithms for modeling the interface between distinct compositions smear the interface at the boundary between compositions, such as methods that add numerical diffusion or 'artificial viscosity' in order to stabilize the algorithm. We present two new algorithms for maintaining high-resolution and sharp computational boundaries in computations of these types of problems: a discontinuous Galerkin method with a bound preserving limiter and a Volume-of-Fluid interface tracking algorithm. We compare these new methods with two approaches widely used for modeling the advection of two distinct thermally driven compositional fields in mantle convection computations: a high-order accurate finite element advection algorithm with entropy viscosity and a particle method that carries a scalar quantity representing the location of each compositional field. All four algorithms are implemented in the open source finite

  10. Application of Prodrugs to Inflammatory Diseases of the Gut

    Directory of Open Access Journals (Sweden)

    Jeffrey L. Ebersole

    2008-02-01

    Full Text Available Oral delivery is the most common and preferred route of drug administrationalthough the digestive tract exhibits several obstacles to drug delivery including motilityand intraluminal pH profiles. The gut milieu represents the largest mucosal surfaceexposed to microorganisms with 1010-12 colony forming bacteria/g of colonic content.Approximately, one third of fecal dry matter is made of bacteria/ bacterial components.Indeed, the normal gut microbiota is responsible for healthy digestion of dietary fibers(polysaccharides and fermentation of short chain fatty acids such as acetate and butyratethat provide carbon sources (fuel for these bacteria. Inflammatory bowel disease (IBDresults in breakage of the mucosal barrier, an altered microbiota and dysregulated gutimmunity. Prodrugs that are chemically constructed to target colonic release or aredegraded specifically by colonic bacteria, can be useful in the treatment of IBD. Thisreview describes the progress in digestive tract prodrug design and delivery in light of gutmetabolic activities.

  11. Saliva-catalyzed hydrolysis of a ketobemidone ester prodrug

    DEFF Research Database (Denmark)

    Hansen, L.B.; Christrup, Lona Louring; Bundgaard, H.

    1992-01-01

    Saliva enzyme-catalysed hydrolysis of ester prodrugs or drugs containing sensitive ester groups may be a limiting factor for the buccal absorption of such compounds. Using the isopropyl carbonate ester of ketobemidone as a model substance of a hydrolysis-sensitive prodrug the esterase activity...... of human saliva has been characterized as a function of various factors. The esterase activity was found to decrease rapidly upon storage of the saliva at 37°C. The activity increased with increasing pH in the range 4.5-7.4 and with increasing salivation flow rate up to a rate of 0.9 ml min. Under resting...... conditions, the flow rate was about 0.2 ml min which implied a greatly decreased esterase activity. The activity was highest after fasting and decreased after intake of a meal. The intraindividual variation in the saliva esterase activity was small whereas a larger interindividual variation was found....

  12. An equivalent fluid/equivalent medium approach for the numerical simulation of coastal landslides propagation: theory and case studies

    OpenAIRE

    P. Mazzanti; F. Bozzano

    2009-01-01

    Coastal and subaqueous landslides can be very dangerous phenomena since they are characterised by the additional risk of induced tsunamis, unlike their completely-subaerial counterparts. Numerical modelling of landslides propagation is a key step in forecasting the consequences of landslides. In this paper, a novel approach named Equivalent Fluid/Equivalent Medium (EFEM) has been developed. It adapts common numerical models and software that were originally designed for subaerial landslides i...

  13. Puromycin-sensitive aminopeptidase: an antiviral prodrug activating enzyme.

    Science.gov (United States)

    Tehler, Ulrika; Nelson, Cara H; Peterson, Larryn W; Provoda, Chester J; Hilfinger, John M; Lee, Kyung-Dall; McKenna, Charles E; Amidon, Gordon L

    2010-03-01

    Cidofovir (HPMPC) is a broad-spectrum antiviral agent, currently used to treat AIDS-related human cytomegalovirus retinitis. Cidofovir has recognized therapeutic potential for orthopox virus infections, although its use is hampered by its inherent low oral bioavailability. Val-Ser-cyclic HPMPC (Val-Ser-cHPMPC) is a promising peptide prodrug which has previously been shown by us to improve the permeability and bioavailability of the parent compound in rodent models (Eriksson et al., 2008. Molecular Pharmaceutics 5, 598-609). Puromycin-sensitive aminopeptidase was partially purified from Caco-2 cell homogenates and identified as a prodrug activating enzyme for Val-Ser-cHPMPC. The prodrug activation process initially involves an enzymatic step where the l-Valine residue is removed by puromycin-sensitive aminopeptidase, a step that is bestatin-sensitive. Subsequent chemical hydrolysis results in the generation of cHPMPC. A recombinant puromycin-sensitive aminopeptidase was generated and its substrate specificity investigated. The k(cat) for Val-pNA was significantly lower than that for Ala-pNA, suggesting that some amino acids are preferred over others. Furthermore, the three-fold higher k(cat) for Val-Ser-cHPMPC as compared to Val-pNA suggests that the leaving group may play an important role in determining hydrolytic activity. In addition to its ability to hydrolyze a variety of substrates, these observations strongly suggest that puromycin-sensitive aminopeptidase is an important enzyme for activating Val-Ser-cHPMPC in vivo. Taken together, our data suggest that puromycin-sensitive aminopeptidase makes an attractive target for future prodrug design.

  14. Classifying the Sizes of Explosive Eruptions using Tephra Deposits: The Advantages of a Numerical Inversion Approach

    Science.gov (United States)

    Connor, C.; Connor, L.; White, J.

    2015-12-01

    Explosive volcanic eruptions are often classified by deposit mass and eruption column height. How well are these eruption parameters determined in older deposits, and how well can we reduce uncertainty using robust numerical and statistical methods? We describe an efficient and effective inversion and uncertainty quantification approach for estimating eruption parameters given a dataset of tephra deposit thickness and granulometry. The inversion and uncertainty quantification is implemented using the open-source PEST++ code. Inversion with PEST++ can be used with a variety of forward models and here is applied using Tephra2, a code that simulates advective and dispersive tephra transport and deposition. The Levenburg-Marquardt algorithm is combined with formal Tikhonov and subspace regularization to invert eruption parameters; a linear equation for conditional uncertainty propagation is used to estimate posterior parameter uncertainty. Both the inversion and uncertainty analysis support simultaneous analysis of the full eruption and wind-field parameterization. The combined inversion/uncertainty-quantification approach is applied to the 1992 eruption of Cerro Negro (Nicaragua), the 2011 Kirishima-Shinmoedake (Japan), and the 1913 Colima (Mexico) eruptions. These examples show that although eruption mass uncertainty is reduced by inversion against tephra isomass data, considerable uncertainty remains for many eruption and wind-field parameters, such as eruption column height. Supplementing the inversion dataset with tephra granulometry data is shown to further reduce the uncertainty of most eruption and wind-field parameters. We think the use of such robust models provides a better understanding of uncertainty in eruption parameters, and hence eruption classification, than is possible with more qualitative methods that are widely used.

  15. Effect of concrete strength gradation to the compressive strength of graded concrete, a numerical approach

    Science.gov (United States)

    Pratama, M. Mirza Abdillah; Aylie, Han; Gan, Buntara Sthenly; Umniati, B. Sri; Risdanareni, Puput; Fauziyah, Shifa

    2017-09-01

    Concrete casting, compacting method, and characteristic of the concrete material determine the performance of concrete as building element due to the material uniformity issue. Previous studies show that gradation in strength exists on building member by nature and negatively influence the load carrying capacity of the member. A pilot research had modeled the concrete gradation in strength with controllable variable and observed that the weakest material determines the strength of graded concrete through uniaxial compressive loading test. This research intends to confirm the recent finding by a numerical approach with extensive variables of strength disparity. The finite element analysis was conducted using the Strand7 nonlinear program. The results displayed that the increase of strength disparity in graded concrete models leads to the slight reduction of models strength. A substantial difference in displacement response is encountered on the models for the small disparity of concrete strength. However, the higher strength of concrete mix in the graded concrete models contributes to the rise of material stiffness that provides a beneficial purpose for serviceability of building members.

  16. Numerical evaluation of the bispectrum in multiple field inflation—the transport approach with code

    Energy Technology Data Exchange (ETDEWEB)

    Dias, Mafalda; Frazer, Jonathan [Theory Group, Deutsches Elektronen-Synchrotron, DESY, D-22603, Hamburg (Germany); Mulryne, David J. [School of Physics and Astronomy, Queen Mary University of London, Mile End Road, London E1 4NS (United Kingdom); Seery, David, E-mail: mafalda.dias@desy.de, E-mail: jonathan.frazer@desy.de, E-mail: d.mulryne@qmul.ac.uk, E-mail: D.Seery@sussex.ac.uk [Astronomy Centre, University of Sussex, Falmer, Brighton BN1 9QH (United Kingdom)

    2016-12-01

    We present a complete framework for numerical calculation of the power spectrum and bispectrum in canonical inflation with an arbitrary number of light or heavy fields. Our method includes all relevant effects at tree-level in the loop expansion, including (i) interference between growing and decaying modes near horizon exit; (ii) correlation and coupling between species near horizon exit and on superhorizon scales; (iii) contributions from mass terms; and (iv) all contributions from coupling to gravity. We track the evolution of each correlation function from the vacuum state through horizon exit and the superhorizon regime, with no need to match quantum and classical parts of the calculation; when integrated, our approach corresponds exactly with the tree-level Schwinger or 'in-in' formulation of quantum field theory. In this paper we give the equations necessary to evolve all two- and three-point correlation functions together with suitable initial conditions. The final formalism is suitable to compute the amplitude, shape, and scale dependence of the bispectrum in models with | f {sub NL}| of order unity or less, which are a target for future galaxy surveys such as Euclid, DESI and LSST. As an illustration we apply our framework to a number of examples, obtaining quantitatively accurate predictions for their bispectra for the first time. Two accompanying reports describe publicly-available software packages that implement the method.

  17. Numerical evaluation of the bispectrum in multiple field inflation—the transport approach with code

    International Nuclear Information System (INIS)

    Dias, Mafalda; Frazer, Jonathan; Mulryne, David J.; Seery, David

    2016-01-01

    We present a complete framework for numerical calculation of the power spectrum and bispectrum in canonical inflation with an arbitrary number of light or heavy fields. Our method includes all relevant effects at tree-level in the loop expansion, including (i) interference between growing and decaying modes near horizon exit; (ii) correlation and coupling between species near horizon exit and on superhorizon scales; (iii) contributions from mass terms; and (iv) all contributions from coupling to gravity. We track the evolution of each correlation function from the vacuum state through horizon exit and the superhorizon regime, with no need to match quantum and classical parts of the calculation; when integrated, our approach corresponds exactly with the tree-level Schwinger or 'in-in' formulation of quantum field theory. In this paper we give the equations necessary to evolve all two- and three-point correlation functions together with suitable initial conditions. The final formalism is suitable to compute the amplitude, shape, and scale dependence of the bispectrum in models with | f NL | of order unity or less, which are a target for future galaxy surveys such as Euclid, DESI and LSST. As an illustration we apply our framework to a number of examples, obtaining quantitatively accurate predictions for their bispectra for the first time. Two accompanying reports describe publicly-available software packages that implement the method.

  18. Numerical evaluation of the bispectrum in multiple field inflation. The transport approach with code

    International Nuclear Information System (INIS)

    Dias, Mafalda; Mulryne, David J.; Seery, David

    2016-09-01

    We present a complete framework for numerical calculation of the power spectrum and bispectrum in canonical inflation with an arbitrary number of light or heavy fields. Our method includes all relevant effects at tree-level in the loop expansion, including (i) interference between growing and decaying modes near horizon exit; (ii) correlation and coupling between species near horizon exit and on superhorizon scales; (iii) contributions from mass terms; and (iv) all contributions from coupling to gravity. We track the evolution of each correlation function from the vacuum state through horizon exit and the superhorizon regime, with no need to match quantum and classical parts of the calculation; when integrated, our approach corresponds exactly with the tree-level Schwinger or 'in-in' formulation of quantum field theory. In this paper we give the equations necessary to evolve all two- and three-point correlation functions together with suitable initial conditions. The final formalism is suitable to compute the amplitude, shape, and scale dependence of the bispectrum in models with vertical stroke f_N_L vertical stroke of order unity or less, which are a target for future galaxy surveys such as Euclid, DESI and LSST. As an illustration we apply our framework to a number of examples, obtaining quantitatively accurate predictions for their bispectra for the first time. Two accompanying reports describe publicly-available software packages that implement the method.

  19. Comparison of maximum runup through analytical and numerical approaches for different fault parameters estimates

    Science.gov (United States)

    Kanoglu, U.; Wronna, M.; Baptista, M. A.; Miranda, J. M. A.

    2017-12-01

    The one-dimensional analytical runup theory in combination with near shore synthetic waveforms is a promising tool for tsunami rapid early warning systems. Its application in realistic cases with complex bathymetry and initial wave condition from inverse modelling have shown that maximum runup values can be estimated reasonably well. In this study we generate a simplistic bathymetry domains which resemble realistic near-shore features. We investigate the accuracy of the analytical runup formulae to the variation of fault source parameters and near-shore bathymetric features. To do this we systematically vary the fault plane parameters to compute the initial tsunami wave condition. Subsequently, we use the initial conditions to run the numerical tsunami model using coupled system of four nested grids and compare the results to the analytical estimates. Variation of the dip angle of the fault plane showed that analytical estimates have less than 10% difference for angles 5-45 degrees in a simple bathymetric domain. These results shows that the use of analytical formulae for fast run up estimates constitutes a very promising approach in a simple bathymetric domain and might be implemented in Hazard Mapping and Early Warning.

  20. Numerical evaluation of the bispectrum in multiple field inflation. The transport approach with code

    Energy Technology Data Exchange (ETDEWEB)

    Dias, Mafalda [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Theory Group; Sussex Univ., Brighton (United Kingdom). Astronomy Centre; Frazer, Jonathan [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Theory Group; Basque Country Univ., Bilbao (Spain). Dept. of Theoretical Physics; IKERBASQUE, Basque Foundation for Science, Bilbao (Spain); Mulryne, David J. [Queen Mary Univ., London (United Kingdom). School of Physics and Astronomy; Seery, David [Sussex Univ., Brighton (United Kingdom). Astronomy Centre

    2016-09-15

    We present a complete framework for numerical calculation of the power spectrum and bispectrum in canonical inflation with an arbitrary number of light or heavy fields. Our method includes all relevant effects at tree-level in the loop expansion, including (i) interference between growing and decaying modes near horizon exit; (ii) correlation and coupling between species near horizon exit and on superhorizon scales; (iii) contributions from mass terms; and (iv) all contributions from coupling to gravity. We track the evolution of each correlation function from the vacuum state through horizon exit and the superhorizon regime, with no need to match quantum and classical parts of the calculation; when integrated, our approach corresponds exactly with the tree-level Schwinger or 'in-in' formulation of quantum field theory. In this paper we give the equations necessary to evolve all two- and three-point correlation functions together with suitable initial conditions. The final formalism is suitable to compute the amplitude, shape, and scale dependence of the bispectrum in models with vertical stroke f{sub NL} vertical stroke of order unity or less, which are a target for future galaxy surveys such as Euclid, DESI and LSST. As an illustration we apply our framework to a number of examples, obtaining quantitatively accurate predictions for their bispectra for the first time. Two accompanying reports describe publicly-available software packages that implement the method.

  1. Comparison of different approaches to the numerical calculation of the LMJ focal

    Directory of Open Access Journals (Sweden)

    Bourgeade A.

    2013-11-01

    Full Text Available The beam smoothing in the focal plane of high power lasers is of particular importance to laser-plasma interaction studies in order to minimize plasma parametric and hydrodynamic instabilities on the target. Here we investigate the focal spot structure in different geometrical configurations where standard paraxial hypotheses are no longer verified. We present numerical studies in the cases of single flat top square beam, LMJ quadruplet and complete ring of quads with large azimuth angle. Different calculations are made with Fresnel diffraction propagation model in the paraxial approximation and full vector Maxwell's equations. The first model is based on Fourier transform from near to far field method. The second model uses first spherical wave decomposition in plane waves with Fourier transform and propagates them to the focal spot. These two different approaches are compared with Miró [1] modeling results using paraxial or Feit and Fleck options. The methods presented here are generic for focal spot calculations. They can be used for other complex geometric configurations and various smoothing techniques. The results will be used as boundary conditions in plasma interaction computations.

  2. In vitro evaluation of dendrimer prodrugs for oral drug delivery.

    Science.gov (United States)

    Najlah, Mohammad; Freeman, Sally; Attwood, David; D'Emanuele, Antony

    2007-05-04

    Dendrimer-based prodrugs were used to enhance the transepithelial permeability of naproxen, a low solubility model drug. The stability of the dendrimer-naproxen link was assessed. Naproxen was conjugated to G0 polyamidoamine (PAMAM) dendrimers either by an amide bond or an ester bond. The stability of G0 prodrugs was evaluated in 80% human plasma and 50% rat liver homogenate. The cytotoxicity of conjugates towards Caco-2 cells was determined and the transport of the conjugates across Caco-2 monolayers (37 degrees C) was reported. In addition, one lauroyl chain (L) was attached to the surface group of G0 PAMAM dendrimer of the diethylene glycol ester conjugate (G0-deg-NAP) to enhance permeability. The lactic ester conjugate, G0-lact-NAP, hydrolyzed slowly in 80% human plasma and in 50% rat liver homogenate (t(1/2)=180 min). G0-deg-NAP was hydrolyzed more rapidly in 80% human plasma (t(1/2)=51 min) and was rapidly cleaved in 50% liver homogenate (t(1/2)=4.7 min). The conjugates were non-toxic when exposed to Caco-2 cells for 3h. Permeability studies showed a significant enhancement in the transport of naproxen when conjugated to dendrimers; L-G0-deg-NAP yielding the highest permeability. Dendrimer-based prodrugs with appropriate linkers have potential as carriers for the oral delivery of low solubility drugs such as naproxen.

  3. Cholesterylbutyrate Solid Lipid Nanoparticles as a Butyric Acid Prodrug

    Directory of Open Access Journals (Sweden)

    Alessandro Mauro

    2008-02-01

    Full Text Available Cholesterylbutyrate (Chol-but was chosen as a prodrug of butyric acid.Butyrate is not often used in vivo because its half-life is very short and therefore too largeamounts of the drug would be necessary for its efficacy. In the last few years butyric acid'santi-inflammatory properties and its inhibitory activity towards histone deacetylases havebeen widely studied, mainly in vitro. Solid Lipid Nanoparticles (SLNs, whose lipid matrixis Chol-but, were prepared to evaluate the delivery system of Chol-but as a prodrug and totest its efficacy in vitro and in vivo. Chol-but SLNs were prepared using the microemulsionmethod; their average diameter is on the order of 100-150 nm and their shape is spherical.The antineoplastic effects of Chol-but SLNs were assessed in vitro on different cancer celllines and in vivo on a rat intracerebral glioma model. The anti-inflammatory activity wasevaluated on adhesion of polymorphonuclear cells to vascular endothelial cells. In thereview we will present data on Chol-but SLNs in vitro and in vivo experiments, discussingthe possible utilisation of nanoparticles for the delivery of prodrugs for neoplastic andchronic inflammatory diseases.

  4. Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs

    Directory of Open Access Journals (Sweden)

    Kazue Kasai

    2013-01-01

    Full Text Available MGH2.1 is a herpes simplex virus type 1 (HSV1 oncolytic virus that expresses two prodrug-activating transgenes: the cyclophosphamide (CPA-activating cytochrome P4502B1 (CYP2B1 and the CPT11-activating secreted human intestinal carboxylesterase (shiCE. Toxicology and biodistribution of MGH2.1 in the presence/absence of prodrugs was evaluated in mice. MGH2.1 ± prodrugs was cytotoxic to human glioma cells, but not to normal cells. Pharmacokinetically, intracranial MGH2.1 did not significantly alter the metabolism of intraperitoneally (i.p. administered prodrugs in mouse plasma, brain, or liver. MGH2.1 did not induce an acute inflammatory reaction. MGH2.1 DNA was detected in brains of mice inoculated with 108 pfus for up to 60 days. However, only one animal showed evidence of viral gene expression at this time. Expression of virally encoded genes was restricted to brain. Intracranial inoculation of MGH2.1 did not induce lethality at 108 pfus in the absence of prodrugs and at 106 pfus in the presence of prodrugs. This study provides safety and toxicology data justifying a possible clinical trial of intratumoral injection of MGH2.1 with peripheral administration of CPA and/or CPT11 prodrugs in humans with malignant gliomas.

  5. Compaction of lanthanide oxide porous microspheres: experimental approach and numerical simulation

    International Nuclear Information System (INIS)

    Parant, Paul

    2016-01-01

    One option envisioned for the future management of high level nuclear waste is the transmutation of minor actinides into short-lived fission products in sodium fast reactor. This route requires the development of pellet fabrication processes to prepare Minor Actinide Bearing Blanket (MABB) for the transmutation of americium. Currently, those ceramic pellets are produced by powder metallurgy processes involving numerous grinding and milling steps that generate very fine and highly contaminating and irradiating particles. a viable option for reducing the amount of those fine particles would be to develop a dustless process by working on much coarser particles. In this context, this study is concerned with the pelletizing of porous and spherical lanthanides oxide precursors (surrogates of actinides). The present work uses both experimental data and numerical simulations to optimize the pelletizing step. The final aim is to obtain, after sintering, homogeneous, dense and undistorted ceramic pellets. Firstly, this study concerns the synthesis and characterization of these oxide microspheres precursors by the Weak acid Resin process, which consists in loading beads of ion exchange resin with lanthanides cations and mineralizing the metal loaded resin leads into sub-millimetric-sized oxide microspheres. Comprehensive characterizations of the microstructure were carried out in function of the synthesis parameters such as calcination temperature, metal nature and diameter size /distribution of the resin beads starting materials to better understand their behaviour into the matrix when producing pellets. Secondly, the mechanical properties of a single microsphere were investigated in order to better understand its behaviour during compaction steps. They were also analysed using multi-scale simulations based on the Discrete Element Method (DEM), which is well suited for such particulate materials. In a second approach, compaction studies were carried out in a three parts die

  6. Theoretical and numerical investigations of TAP experiments. New approaches for variable pressure conditions

    Energy Technology Data Exchange (ETDEWEB)

    Senechal, U.; Breitkopf, C. [Technische Univ. Dresden (Germany). Inst. fuer Energietechnik

    2011-07-01

    Temporal analysis of products (TAP) is a valuable tool for characterization of porous catalytic structures. Established TAP-modeling requires a spatially constant diffusion coefficient and neglect convective flows, which is only valid in Knudsen diffusion regime. Therefore in experiments, the number of molecules per pulse must be chosen accordingly. New approaches for variable process conditions are highly required. Thus, a new theoretical model is developed for estimating the number of molecules per pulse to meet these requirements under any conditions and at any time. The void volume is calculated as the biggest sphere fitting between three pellets. The total number of pulsed molecules is assumed to fill the first void volume at the inlet immediately. Molecule numbers from these calculations can be understood as maximum possible molecules at any time in the reactor to be in Knudsen diffusion regime, i.e., above the Knudsen number of 2. Moreover, a new methodology for generating a full three-dimensional geometrical representation of beds is presented and used for numerical simulations to investigate spatial effects. Based on a freely available open-source game physics engine library (BULLET), beds of arbitrary-sized pellets can be generated and transformed to CFD-usable geometry. In CFD-software (ANSYS CFX registered) a transient diffusive transport equation with time-dependent inlet boundary conditions is solved. Three different pellet diameters were investigated with 1e18 molecules per pulse, which is higher than the limit from the theoretical calculation. Spatial and temporal distributions of transported species show regions inside the reactor, where non-Knudsen conditions exist. From this results, the distance from inlet can be calculated where the theoretical pressure limit (Knudsen number equals 2) is obtained, i.e., from this point to the end of the reactor Knudsen regime can be assumed. Due to linear dependency of pressure and concentration (assuming ideal

  7. Thiazolidinone prodrugs activated by reactive oxygen species for use in the treatment of inflammatory diseases and cancer

    DEFF Research Database (Denmark)

    2018-01-01

    Prodrugs activated predominantly or exclusively in inflammatory tissue, more particularly prodrugs of methotrexate and derivatives thereof, which are selectively activated by Reactive Oxygen Species (ROS) in inflammatory tissues associated with cancer and inflammatory diseases, as well as method...

  8. Bioactivation antioxidant and transglycating properties of N-acetylcarnosine autoinduction prodrug of a dipeptide L-carnosine in mucoadhesive drug delivery eye-drop formulation: powerful eye health application technique and therapeutic platform.

    Science.gov (United States)

    Babizhayev, Mark A

    2012-06-01

    A considerable interest in N-acetylcarnosine ocular drug design for eye health is based on clinical strategies to improve ocular drug delivery through metabolic enzymatic activation. Human biology aspects of ocular N-acetylcarnosine deacetylation during its pass through the cornea to the aqueous humor and dipeptide hydrolyzing enzymes are characterized. Novel approaches to ocular drug delivery increasing intraocular bioavailability of N-acetylcarnosine biologically activated metabolite carnosine become an integral development ensuring prolonged retention of the medication in the mucoadhesive precorneal area and facilitating transcorneal penetration of the natural dipeptide with the corneal promoters. A comprehensive list of techniques for peptide drug design, synthesis, purification, and biological analyses was considered: liquid chromatography (LC), high performance liquid chromatography (HPLC), (1) H and (13) C nuclear magnetic resonance (NMR), electrospray ionization (ESI) mass spectroscopy, and spectrophotometry. The antioxidant activity of therapeutics-targeted molecules was studied in aqueous solution and in a lipid membrane environment. A deglycation therapeutic system was developed involving removal, by transglycation of sugar or aldehyde moieties from Schiff bases by histidyl-hydrazide compounds or aldehyde scavenger L-carnosine. Clinical studies included ophthalmoscopy, visual acuity (VA), halometer disability glare tests, slit-image, and retro-illumination photography. N-acetylcarnosine 1% lubricant eye drops are considered as an auto-induction prodrug and natural ocular redox state balance therapies with implications in prevention and treatment of serious eye diseases that involve pathways of continuous oxidative damage to ocular tissues(cataracts, primary open-angle glaucoma, age-related macular degeneration) and sight-threatening glycosylation processes (diabetic retinopathy and consequent visual impairment) important for public health. The results of

  9. Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs

    Directory of Open Access Journals (Sweden)

    Zaman Ashraf

    2016-12-01

    Full Text Available Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a–c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001 is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06% of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001. The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a–c interacts with the residues present in active binding sites of target protein. The stability of drug–target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug.

  10. A Numerical Approach for Hybrid Simulation of Power System Dynamics Considering Extreme Icing Events

    DEFF Research Database (Denmark)

    Chen, Lizheng; Zhang, Hengxu; Wu, Qiuwei

    2017-01-01

    numerical simulation scheme integrating icing weather events with power system dynamics is proposed to extend power system numerical simulation. A technique is developed to efficiently simulate the interaction of slow dynamics of weather events and fast dynamics of power systems. An extended package for PSS...

  11. Systematic approach in optimizing numerical memory-bound kernels on GPU

    KAUST Repository

    Abdelfattah, Ahmad

    2013-01-01

    The use of GPUs has been very beneficial in accelerating dense linear algebra computational kernels (DLA). Many high performance numerical libraries like CUBLAS, MAGMA, and CULA provide BLAS and LAPACK implementations on GPUs as well as hybrid computations involving both, CPUs and GPUs. GPUs usually score better performance than CPUs for compute-bound operations, especially those characterized by a regular data access pattern. This paper highlights a systematic approach for efficiently implementing memory-bound DLA kernels on GPUs, by taking advantage of the underlying device\\'s architecture (e.g., high throughput). This methodology proved to outperform existing state-of-the-art GPU implementations for the symmetric matrix-vector multiplication (SYMV), characterized by an irregular data access pattern, in a recent work (Abdelfattah et. al, VECPAR 2012). We propose to extend this methodology to the general matrix-vector multiplication (GEMV) kernel. The performance results show that our GEMV implementation achieves better performance for relatively small to medium matrix sizes, making it very influential in calculating the Hessenberg and bidiagonal reductions of general matrices (radar applications), which are the first step toward computing eigenvalues and singular values, respectively. Considering small and medium size matrices (≤4500), our GEMV kernel achieves an average 60% improvement in single precision (SP) and an average 25% in double precision (DP) over existing open-source and commercial software solutions. These results improve reduction algorithms for both small and large matrices. The improved GEMV performances engender an averge 30% (SP) and 15% (DP) in Hessenberg reduction and up to 25% (SP) and 14% (DP) improvement for the bidiagonal reduction over the implementation provided by CUBLAS 5.0. © 2013 Springer-Verlag.

  12. Seismic zonation of Bucharest by using a deterministic approach of numerical modeling

    International Nuclear Information System (INIS)

    Moldoveanu, C.L.; Panza, G.F.; Cioflan, C.; Radulian, M.; Marmureanu, Gh.

    2002-01-01

    Bucharest city represents the largest European center (about 2 million inhabitants and 230 km 2 constructed area) periodically subjected to the strong intermediate-depth earthquakes originating in Vrancea region. The statistics indicate a recurrence interval of 25 years for M w ≥7.0 Vrancea events and a significant earthquake hazard for the city location with a 50% chance for an event of M w >7.6 every 50 years. The strongest Vrancea events of the last century occurred in 1908 (M w =7.1), 1940 (M w =7.7), 1977 (M w =7.4) and 1986 (M w =7.1) and inflicted heavy damage and casualties in Bucharest. Under these circumstances, the ground motion evaluation for the city area represents an essential step toward the mitigation of the local seismic risk. This paper presents the new insights coming from direct instrumental observation and interpretation of the local effects as well as realistic numerical modeling that update and improve the input data necessary for a detailed microzoning map of the Romanian capital. Our results show that the synthetic local hazard distribution we obtain with the deterministic approach supplies a realistic estimation of the seismic input, highly sensitive not only to the local conditions, but also to the source and the path structure parameters. The complex hybrid method we use offers the chance to merge the different specific accumulated information in reasonably well constrained scenarios for a level C realistic microzonation of Bucharest area to be use to mitigate the effects of future strong events originating in Vrancea region. (authors)

  13. Combined analytical and numerical approaches in Dynamic Stability analyses of engineering systems

    Science.gov (United States)

    Náprstek, Jiří

    2015-03-01

    Dynamic Stability is a widely studied area that has attracted many researchers from various disciplines. Although Dynamic Stability is usually associated with mechanics, theoretical physics or other natural and technical disciplines, it is also relevant to social, economic, and philosophical areas of our lives. Therefore, it is useful to occasionally highlight the general aspects of this amazing area, to present some relevant examples and to evaluate its position among the various branches of Rational Mechanics. From this perspective, the aim of this study is to present a brief review concerning the Dynamic Stability problem, its basic definitions and principles, important phenomena, research motivations and applications in engineering. The relationships with relevant systems that are prone to stability loss (encountered in other areas such as physics, other natural sciences and engineering) are also noted. The theoretical background, which is applicable to many disciplines, is presented. In this paper, the most frequently used Dynamic Stability analysis methods are presented in relation to individual dynamic systems that are widely discussed in various engineering branches. In particular, the Lyapunov function and exponent procedures, Routh-Hurwitz, Liénard, and other theorems are outlined together with demonstrations. The possibilities for analytical and numerical procedures are mentioned together with possible feedback from experimental research and testing. The strengths and shortcomings of these approaches are evaluated together with examples of their effective complementing of each other. The systems that are widely encountered in engineering are presented in the form of mathematical models. The analyses of their Dynamic Stability and post-critical behaviour are also presented. The stability limits, bifurcation points, quasi-periodic response processes and chaotic regimes are discussed. The limit cycle existence and stability are examined together with their

  14. Solving the dynamic rupture problem with different numerical approaches and constitutive laws

    Science.gov (United States)

    Bizzarri, A.; Cocco, M.; Andrews, D.J.; Boschi, Enzo

    2001-01-01

    We study the dynamic initiation, propagation and arrest of a 2-D in-plane shear rupture by solving the elastodynamic equation by using both a boundary integral equation method and a finite difference approach. For both methods we adopt different constitutive laws: a slip-weakening (SW) law, with constant weakening rate, and rate- and state-dependent friction laws (Dieterich-Ruina). Our numerical procedures allow the use of heterogeneous distributions of constitutive parameters along the fault for both formulations. We first compare the two solution methods with an SW law, emphasizing the required stability conditions to achieve a good resolution of the cohesive zone and to avoid artificial complexity in the solutions. Our modelling results show that the two methods provide very similar time histories of dynamic source parameters. We point out that, if a careful control of resolution and stability is performed, the two methods yield identical solutions. We have also compared the rupture evolution resulting from an SW and a rate- and state-dependent friction law. This comparison shows that despite the different constitutive formulations, a similar behaviour is simulated during the rupture propagation and arrest. We also observe a crack tip bifurcation and a jump in rupture velocity (approaching the P-wave speed) with the Dieterich-Ruina (DR) law. The rupture arrest at a barrier (high strength zone) and the barrier-healing mechanism are also reproduced by this law. However, this constitutive formulation allows the simulation of a more general and complex variety of rupture behaviours. By assuming different heterogeneous distributions of the initial constitutive parameters, we are able to model a barrier-healing as well as a self-healing process. This result suggests that if the heterogeneity of the constitutive parameters is taken into account, the different healing mechanisms can be simulated. We also study the nucleation phase duration Tn, defined as the time

  15. Analytic-Numerical Approach to Solving Singularly Perturbed Parabolic Equations with the Use of Dynamic Adapted Meshes

    Directory of Open Access Journals (Sweden)

    D. V. Lukyanenko

    2016-01-01

    Full Text Available The main objective of the paper is to present a new analytic-numerical approach to singularly perturbed reaction-diffusion-advection models with solutions containing moving interior layers (fronts. We describe some methods to generate the dynamic adapted meshes for an efficient numerical solution of such problems. It is based on a priori information about the moving front properties provided by the asymptotic analysis. In particular, for the mesh construction we take into account a priori asymptotic evaluation of the location and speed of the moving front, its width and structure. Our algorithms significantly reduce the CPU time and enhance the stability of the numerical process compared with classical approaches.The article is published in the authors’ wording.

  16. Variation of Student Numerical and Figural Reasoning Approaches by Pattern Generalization Type, Strategy Use and Grade Level

    Science.gov (United States)

    El Mouhayar, Rabih; Jurdak, Murad

    2016-01-01

    This paper explored variation of student numerical and figural reasoning approaches across different pattern generalization types and across grade level. An instrument was designed for this purpose. The instrument was given to a sample of 1232 students from grades 4 to 11 from five schools in Lebanon. Analysis of data showed that the numerical…

  17. A numerical approach to the study of the perpetual case of Ameripean options

    Science.gov (United States)

    Kandilarov, J.

    2013-12-01

    A new numerical method for solving the perpetual case of Ameripean options is proposed. The Ameripean delayed exercise model analyzes a new class of option model with American and ParAsian features. The model is mathematically described by ultraparabolic and parabolic PDE's which are valid over different regions. The perpetual case leads to the parabolic-elliptic two-phase Stefan problem with free internal boundary. To deal with the obtained nonlinear problem an iterative numerical method is proposed. Numerical analysis are presented and discussed.

  18. A Numerical Approach to Solving an Inverse Heat Conduction Problem Using the Levenberg-Marquardt Algorithm

    Directory of Open Access Journals (Sweden)

    Tao Min

    2014-01-01

    Full Text Available This paper is intended to provide a numerical algorithm involving the combined use of the Levenberg-Marquardt algorithm and the Galerkin finite element method for estimating the diffusion coefficient in an inverse heat conduction problem (IHCP. In the present study, the functional form of the diffusion coefficient is unknown a priori. The unknown diffusion coefficient is approximated by the polynomial form and the present numerical algorithm is employed to find the solution. Numerical experiments are presented to show the efficiency of the proposed method.

  19. Modeling of Coaxial Slot Waveguides Using Analytical and Numerical Approaches: Revisited

    Directory of Open Access Journals (Sweden)

    Kok Yeow You

    2012-01-01

    Full Text Available Our reviews of analytical methods and numerical methods for coaxial slot waveguides are presented. The theories, background, and physical principles related to frequency-domain electromagnetic equations for coaxial waveguides are reassessed. Comparisons of the accuracies of various types of admittance and impedance equations and numerical simulations are made, and the fringing field at the aperture sensor, which is represented by the lumped capacitance circuit, is evaluated. The accuracy and limitations of the analytical equations are explained in detail. The reasons for the replacement of analytical methods by numerical methods are outlined.

  20. The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

    Directory of Open Access Journals (Sweden)

    Yasuhiro Tsume

    2014-01-01

    Full Text Available Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.

  1. Pharmacokinetics of intravitreal 5-flurouracil prodrugs in silicone oil. Experimental studies in pigs

    DEFF Research Database (Denmark)

    Laugesen, Caroline S; Steffansen, Bente; Scherfig, Erik

    2005-01-01

    PURPOSE: To examine the in vivo pharmacokinetics of intravitreal 5-Fluorouracil (5-FU) following tamponade with 5-FU prodrug silicone oil formulations. METHOD: Two different alkoxycarbonyl 5-FU prodrugs denoted C12 and C18 were synthesized and formulated as silicone oil suspensions. A total of 26...

  2. The dipeptide monoester prodrugs of floxuridine and gemcitabine-feasibility of orally administrable nucleoside analogs.

    Science.gov (United States)

    Tsume, Yasuhiro; Borras Bermejo, Blanca; Amidon, Gordon L

    2014-01-27

    Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.

  3. The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

    Science.gov (United States)

    Tsume, Yasuhiro; Bermejo, Blanca Borras; Amidon, Gordon L.

    2014-01-01

    Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5′-l-phenylalanyl-l-tyrosyl-floxuridine and 5′-l-phenylalanyl-l-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents. PMID:24473270

  4. The efficacy of the anthracycline prodrug daunorubicin-GA3 in human ovarian cancer xenografts

    NARCIS (Netherlands)

    Houba, PHJ; Boven, E; Erkelens, CAM; Leenders, RGG; Scheeren, JW; Pinedo, HM; Haisma, HJ

    1998-01-01

    The prodrug N-[4-(daunorubicin-N-carbonyl-oxymethyl)phenyl] O-beta-glucuronyl carbamate (DNR-GA3) was synthesized for specific activation by human beta-glucuronidase, released in necrotic areas of tumour lesions. In vitro, DNR-GA3 was 18 times less toxic than daunorubicin (DNR) and the prodrug was

  5. Paclitaxel prodrugs, method for preparation as well as their use in selective chemotherapy

    NARCIS (Netherlands)

    de Bont, Hendricus BA; Leenders, Ruben GG; Scheeren, Johan W; Haisma, Hidde J; de Vos, Dick

    1998-01-01

    A paclitaxel prodrug has a paclitaxel portion coupled to a cleavable N-(aliphatic or aromatic)-O-glycosyl carbamate spacer group, and can be administered orally, topically or by injection to provide an anti-tumor effect, the prodrug being activated by a hydrolizing enzyme, an endogeneous enzyme or

  6. Fabrication of Hyperbranched Block-Statistical Copolymer-Based Prodrug with Dual Sensitivities for Controlled Release.

    Science.gov (United States)

    Zheng, Luping; Wang, Yunfei; Zhang, Xianshuo; Ma, Liwei; Wang, Baoyan; Ji, Xiangling; Wei, Hua

    2018-01-17

    La cells. Interestingly, the simultaneous application of both acidic pH and GSH triggers promoted significantly the cleavage and release of CPT compared to the exertion of single trigger. This study thus developed a facile approach toward hyperbranched polymer-based prodrugs with high therapeutic efficacy for anticancer drug delivery.

  7. On the physical and chemical details of alumina atomic layer deposition: A combined experimental and numerical approach

    International Nuclear Information System (INIS)

    Pan, Dongqing; Ma, Lulu; Xie, Yuanyuan; Yuan, Chris; Jen, Tien Chien

    2015-01-01

    Alumina thin film is typically studied as a model atomic layer deposition (ALD) process due to its high dielectric constant, high thermal stability, and good adhesion on various wafer surfaces. Despite extensive applications of alumina ALD in microelectronics industries, details on the physical and chemical processes are not yet well understood. ALD experiments are not able to shed adequate light on the detailed information regarding the transient ALD process. Most of current numerical approaches lack detailed surface reaction mechanisms, and their results are not well correlated with experimental observations. In this paper, the authors present a combined experimental and numerical study on the details of flow and surface reactions in alumina ALD using trimethylaluminum and water as precursors. Results obtained from experiments and simulations are compared and correlated. By experiments, growth rate on five samples under different deposition conditions is characterized. The deposition rate from numerical simulation agrees well with the experimental results. Details of precursor distributions in a full cycle of ALD are studied numerically to bridge between experimental observations and simulations. The 3D transient numerical model adopts surface reaction kinetics and mechanisms based on atomic-level studies to investigate the surface deposition process. Surface deposition is shown as a strictly self-limited process in our numerical studies. ALD is a complex strong-coupled fluid, thermal and chemical process, which is not only heavily dependent on the chemical kinetics and surface conditions but also on the flow and material distributions

  8. Pricing index-based catastrophe bonds: Part 1: Formulation and discretization issues using a numerical PDE approach

    Science.gov (United States)

    Unger, André J. A.

    2010-02-01

    This work is the first installment in a two-part series, and focuses on the development of a numerical PDE approach to price components of a Bermudan-style callable catastrophe (CAT) bond. The bond is based on two underlying stochastic variables; the PCS index which posts quarterly estimates of industry-wide hurricane losses as well as a single-factor CIR interest rate model for the three-month LIBOR. The aggregate PCS index is analogous to losses claimed under traditional reinsurance in that it is used to specify a reinsurance layer. The proposed CAT bond model contains a Bermudan-style call feature designed to allow the reinsurer to minimize their interest rate risk exposure on making substantial fixed coupon payments using capital from the reinsurance premium. Numerical PDE methods are the fundamental strategy for pricing early-exercise constraints, such as the Bermudan-style call feature, into contingent claim models. Therefore, the objective and unique contribution of this first installment in the two-part series is to develop a formulation and discretization strategy for the proposed CAT bond model utilizing a numerical PDE approach. Object-oriented code design is fundamental to the numerical methods used to aggregate the PCS index, and implement the call feature. Therefore, object-oriented design issues that relate specifically to the development of a numerical PDE approach for the component of the proposed CAT bond model that depends on the PCS index and LIBOR are described here. Formulation, numerical methods and code design issues that relate to aggregating the PCS index and introducing the call option are the subject of the companion paper.

  9. The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Green, Laura K.; Storey, Mathew A. [School of Biological Sciences, Victoria University of Wellington, Kelburn Parade, Wellington 6140 (New Zealand); Williams, Elsie M. [School of Biological Sciences, Victoria University of Wellington, Kelburn Parade, Wellington 6140 (New Zealand); Victoria University Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington, Wellington 6140 (New Zealand); Patterson, Adam V.; Smaill, Jeff B. [Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland 1142 (New Zealand); Auckland Cancer Society Research Centre, University of Auckland, Grafton, Auckland 1142 (New Zealand); Copp, Janine N.; Ackerley, David F., E-mail: david.ackerley@vuw.ac.nz [School of Biological Sciences, Victoria University of Wellington, Kelburn Parade, Wellington 6140 (New Zealand); Victoria University Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington, Wellington 6140 (New Zealand); Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland 1142 (New Zealand)

    2013-08-08

    Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy (GDEPT). Two promising hypoxia prodrugs for GDEPT are the dinitrobenzamide mustard PR-104A, and the nitrochloromethylbenzindoline prodrug nitro-CBI-DEI. We describe here use of a nitro-quenched fluorogenic probe to identify MsuE from Pseudomonas aeruginosa as a novel nitroreductase candidate for GDEPT. In SOS and bacteria-delivered enzyme prodrug cytotoxicity assays MsuE was less effective at activating CB1954 (a first-generation GDEPT prodrug) than the “gold standard” nitroreductases NfsA and NfsB from Escherichia coli. However, MsuE exhibited comparable levels of activity with PR-104A and nitro-CBI-DEI, and is the first nitroreductase outside of the NfsA and NfsB enzyme families to do so. These in vitro findings suggest that MsuE is worthy of further evaluation in in vivo models of GDEPT.

  10. The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy

    International Nuclear Information System (INIS)

    Green, Laura K.; Storey, Mathew A.; Williams, Elsie M.; Patterson, Adam V.; Smaill, Jeff B.; Copp, Janine N.; Ackerley, David F.

    2013-01-01

    Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy (GDEPT). Two promising hypoxia prodrugs for GDEPT are the dinitrobenzamide mustard PR-104A, and the nitrochloromethylbenzindoline prodrug nitro-CBI-DEI. We describe here use of a nitro-quenched fluorogenic probe to identify MsuE from Pseudomonas aeruginosa as a novel nitroreductase candidate for GDEPT. In SOS and bacteria-delivered enzyme prodrug cytotoxicity assays MsuE was less effective at activating CB1954 (a first-generation GDEPT prodrug) than the “gold standard” nitroreductases NfsA and NfsB from Escherichia coli. However, MsuE exhibited comparable levels of activity with PR-104A and nitro-CBI-DEI, and is the first nitroreductase outside of the NfsA and NfsB enzyme families to do so. These in vitro findings suggest that MsuE is worthy of further evaluation in in vivo models of GDEPT

  11. A natural approach to convey numerical digits using hand activity recognition based on hand shape features

    Science.gov (United States)

    Chidananda, H.; Reddy, T. Hanumantha

    2017-06-01

    This paper presents a natural representation of numerical digit(s) using hand activity analysis based on number of fingers out stretched for each numerical digit in sequence extracted from a video. The analysis is based on determining a set of six features from a hand image. The most important features used from each frame in a video are the first fingertip from top, palm-line, palm-center, valley points between the fingers exists above the palm-line. Using this work user can convey any number of numerical digits using right or left or both the hands naturally in a video. Each numerical digit ranges from 0 to9. Hands (right/left/both) used to convey digits can be recognized accurately using the valley points and with this recognition whether the user is a right / left handed person in practice can be analyzed. In this work, first the hand(s) and face parts are detected by using YCbCr color space and face part is removed by using ellipse based method. Then, the hand(s) are analyzed to recognize the activity that represents a series of numerical digits in a video. This work uses pixel continuity algorithm using 2D coordinate geometry system and does not use regular use of calculus, contours, convex hull and datasets.

  12. A novel Lagrangian approach for the stable numerical simulation of fault and fracture mechanics

    Energy Technology Data Exchange (ETDEWEB)

    Franceschini, Andrea; Ferronato, Massimiliano, E-mail: massimiliano.ferronato@unipd.it; Janna, Carlo; Teatini, Pietro

    2016-06-01

    The simulation of the mechanics of geological faults and fractures is of paramount importance in several applications, such as ensuring the safety of the underground storage of wastes and hydrocarbons or predicting the possible seismicity triggered by the production and injection of subsurface fluids. However, the stable numerical modeling of ground ruptures is still an open issue. The present work introduces a novel formulation based on the use of the Lagrange multipliers to prescribe the constraints on the contact surfaces. The variational formulation is modified in order to take into account the frictional work along the activated fault portion according to the principle of maximum plastic dissipation. The numerical model, developed in the framework of the Finite Element method, provides stable solutions with a fast convergence of the non-linear problem. The stabilizing properties of the proposed model are emphasized with the aid of a realistic numerical example dealing with the generation of ground fractures due to groundwater withdrawal in arid regions. - Highlights: • A numerical model is developed for the simulation of fault and fracture mechanics. • The model is implemented in the framework of the Finite Element method and with the aid of Lagrange multipliers. • The proposed formulation introduces a new contribution due to the frictional work on the portion of activated fault. • The resulting algorithm is highly non-linear as the portion of activated fault is itself unknown. • The numerical solution is validated against analytical results and proves to be stable also in realistic applications.

  13. A novel Lagrangian approach for the stable numerical simulation of fault and fracture mechanics

    International Nuclear Information System (INIS)

    Franceschini, Andrea; Ferronato, Massimiliano; Janna, Carlo; Teatini, Pietro

    2016-01-01

    The simulation of the mechanics of geological faults and fractures is of paramount importance in several applications, such as ensuring the safety of the underground storage of wastes and hydrocarbons or predicting the possible seismicity triggered by the production and injection of subsurface fluids. However, the stable numerical modeling of ground ruptures is still an open issue. The present work introduces a novel formulation based on the use of the Lagrange multipliers to prescribe the constraints on the contact surfaces. The variational formulation is modified in order to take into account the frictional work along the activated fault portion according to the principle of maximum plastic dissipation. The numerical model, developed in the framework of the Finite Element method, provides stable solutions with a fast convergence of the non-linear problem. The stabilizing properties of the proposed model are emphasized with the aid of a realistic numerical example dealing with the generation of ground fractures due to groundwater withdrawal in arid regions. - Highlights: • A numerical model is developed for the simulation of fault and fracture mechanics. • The model is implemented in the framework of the Finite Element method and with the aid of Lagrange multipliers. • The proposed formulation introduces a new contribution due to the frictional work on the portion of activated fault. • The resulting algorithm is highly non-linear as the portion of activated fault is itself unknown. • The numerical solution is validated against analytical results and proves to be stable also in realistic applications.

  14. Thapsigargin, origin, chemistry, structure-activity relationships and prodrug development

    DEFF Research Database (Denmark)

    Doan, Thi Quynh Nhu; Christensen, Søren Brøgger

    2015-01-01

    Thapsigargin was originally isolated from the roots of the Mediterranean umbelliferous plant Thapsia garganica in order to characterize the skin irritant principle. The biological activity was related to the subnanomolar affinity for the sarco-endoplasmic reticulum calcium ATPase. Prolonged......) targeted against prostate cancer. Conjugation to a peptide, which only is a substrate for prostate specific membrane antigen enabled development of a prodrug (G202), which is targeted towards a number of cancer diseases including hepatocellular carcinoma. G202 has under the name of mipsagargin in clinical...

  15. A novel Lagrangian approach for the stable numerical simulation of fault and fracture mechanics

    Science.gov (United States)

    Franceschini, Andrea; Ferronato, Massimiliano; Janna, Carlo; Teatini, Pietro

    2016-06-01

    The simulation of the mechanics of geological faults and fractures is of paramount importance in several applications, such as ensuring the safety of the underground storage of wastes and hydrocarbons or predicting the possible seismicity triggered by the production and injection of subsurface fluids. However, the stable numerical modeling of ground ruptures is still an open issue. The present work introduces a novel formulation based on the use of the Lagrange multipliers to prescribe the constraints on the contact surfaces. The variational formulation is modified in order to take into account the frictional work along the activated fault portion according to the principle of maximum plastic dissipation. The numerical model, developed in the framework of the Finite Element method, provides stable solutions with a fast convergence of the non-linear problem. The stabilizing properties of the proposed model are emphasized with the aid of a realistic numerical example dealing with the generation of ground fractures due to groundwater withdrawal in arid regions.

  16. Local impact effects on concrete target due to missile: An empirical and numerical approach

    International Nuclear Information System (INIS)

    Ranjan, Rajiv; Banerjee, Sauvik; Singh, R.K.; Banerji, Pradipta

    2014-01-01

    Highlights: • Local impact effect of hard missile on reinforced concrete targets has been studied. • Review of empirical formulation for predicting local response carried out. • Numerical simulation of experimental test of Kojima (1991) carried out. • Divergence of FE results with those obtained using emperical formulations. • Close match of numerical simulation results with experimental data. - Abstract: Concrete containment walls and internal concrete barrier walls of a Nuclear Power Plant safety related structures are often required to be designed for externally and internally generated missiles. Potential missiles include external extreme wind generated missiles, aircraft crash and internal accident generated missiles such as impact due to turbine blade failure and steel pipe missiles resulting from pipe break. The objective of the present paper is to compare local missile impact effects on reinforced concrete target using available empirical formulations with those obtained using LS-DYNA numerical simulation. The use of numerical simulations for capturing the transient structural response has become increasingly used for structural design against impact loads. They overcome the limits of applicability of the empirical formulae and also provide information on stress and deformation fields, which may be used to improve the resistance of the concrete. Finite element (FE) analyses of an experimental impact problem reported by Kojima (1991) are carried out that are able to capture the missile impact effects; in terms of local and global damage. The continuous surface cap model has been used for modelling concrete behaviour. A range of missile velocity has been considered to simulate local missile impact phenomenon and modes of failure and to capture the concrete response from elastic to plastic fracture. A comparison is then made between the empirical formulations, numerical simulation results, and available experimental results of slab impact tests

  17. Identification of oxidized protein hydrolase as a potential prodrug target in prostate cancer

    International Nuclear Information System (INIS)

    McGoldrick, Christopher A; Jiang, Yu-Lin; Paromov, Victor; Brannon, Marianne; Krishnan, Koyamangalath; Stone, William L

    2014-01-01

    Esterases are often overexpressed in cancer cells and can have chiral specificities different from that of the corresponding normal tissues. For this reason, ester prodrugs could be a promising approach in chemotherapy. In this study, we focused on the identification and characterization of differentially expressed esterases between non-tumorigenic and tumorigenic prostate epithelial cells. Cellular lysates from LNCaP, DU 145, and PC3 prostate cancer cell lines, tumorigenic RWPE-2 prostate epithelial cells, and non-tumorigenic RWPE-1 prostate epithelial cells were separated by native polyacrylamide gel electrophoresis (n-PAGE) and the esterase activity bands visualized using α-naphthyl acetate or α-naphthyl-N-acetylalaninate (ANAA) chiral esters and Fast Blue RR salt. The esterases were identified using nanospray LC/MS-MS tandem mass spectrometry and confirmed by Western blotting, native electroblotting, inhibition assays, and activity towards a known specific substrate. The serine protease/esterase oxidized protein hydrolase (OPH) was overexpressed in COS-7 cells to verify our results. The major esterase observed with the ANAA substrates within the n-PAGE activity bands was identified as OPH. OPH (EC 3.4.19.1) is a serine protease/esterase and a member of the prolyl oligopeptidase family. We found that LNCaP lysates contained approximately 40% more OPH compared to RWPE-1 lysates. RWPE-2, DU145 and PC3 cell lysates had similar levels of OPH activity. OPH within all of the cell lysates tested had a chiral preference for the S-isomer of ANAA. LNCaP cells were stained more intensely with ANAA substrates than RWPE-1 cells and COS-7 cells overexpressing OPH were found to have a higher activity towards the ANAA and AcApNA than parent COS-7 cells. These data suggest that prodrug derivatives of ANAA and AcApNA could have potential as chemotherapeutic agents for the treatment of prostate cancer tumors that overexpress OPH

  18. Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models.

    Science.gov (United States)

    Benito, Juliana; Ramirez, Marc S; Millward, Niki Zacharias; Velez, Juliana; Harutyunyan, Karine G; Lu, Hongbo; Shi, Yue-Xi; Matre, Polina; Jacamo, Rodrigo; Ma, Helen; Konoplev, Sergej; McQueen, Teresa; Volgin, Andrei; Protopopova, Marina; Mu, Hong; Lee, Jaehyuk; Bhattacharya, Pratip K; Marszalek, Joseph R; Davis, R Eric; Bankson, James A; Cortes, Jorge E; Hart, Charles P; Andreeff, Michael; Konopleva, Marina

    2016-04-01

    To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models. Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models. Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells. These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. ©2015 American Association for Cancer Research.

  19. Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition.

    Science.gov (United States)

    Meng, Fanying; Bhupathi, Deepthi; Sun, Jessica D; Liu, Qian; Ahluwalia, Dharmendra; Wang, Yan; Matteucci, Mark D; Hart, Charles P

    2015-05-21

    The hypoxia-activated prodrug TH-302 is reduced at its nitroimidazole group and selectively under hypoxic conditions releases the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Here, we have explored the effect of Chk1 inhibition on TH-302-mediated pharmacological activities. We employed in vitro cell viability, DNA damage, cellular signaling assays and the in vivo HT29 human tumor xenograft model to study the effect of Chk1inhibition on TH-302 antitumor activities. TH-302 cytotoxicity is greatly enhanced by Chk1 inhibition in p53-deficient but not in p53-proficient human cancer cell lines. Chk1 inhibitors reduced TH-302-induced cell cycle arrest via blocking TH-302-induced decrease of phosphorylation of histone H3 and increasing Cdc2-Y15 phosphorylation. Employing the single-cell gel electrophoresis (comet) assay, we observed a potentiation of the TH-302 dependent tail moment. TH-302 induced γH2AX and apoptosis were also increased upon the addition of Chk1 inhibitor. Potentiation of TH-302 cytotoxicity by Chk1 inhibitor was only observed in cell lines proficient in, but not deficient in homology-directed DNA repair. We also show that combination treatment led to lowering of Rad51 expression levels as compared to either agent alone. In vivo data demonstrate that Chk1 inhibitor enhances TH-302 anti-tumor activity in p53 mutant HT-29 human tumor xenografts, supporting the hypothesis that these in vitro results can translate to enhanced in vivo efficacy of the combination. TH-302-mediated in vitro and in vivo anti-tumor activities were greatly enhanced by the addition of Chk1 inhibitors. The preclinical data presented in this study support a new approach for the treatment of p53-deficient hypoxic cancers by combining Chk1 inhibitors with the hypoxia-activated prodrug TH-302.

  20. A numerical approach to calculate the induced voltage in the case of conduced perturbations

    Energy Technology Data Exchange (ETDEWEB)

    Andretzko, J.P.; Hedjiedj, A.; Babouri, A.; Guendouz, L.; Nadi, M. [Nancy-1 Univ. Henri Poincare, Lab. d' Instrumentation Electronique de Nancy, Faculte des Sciences, 54 - Vandoeuvre les Nancy (France)

    2006-07-01

    This paper presents a method of numerical simulation that makes it possible to calculate the induced tension to the terminals of the cardiac pacemaker subjected to conduced disturbances. The physical model used for simulation is an experimental test bed which makes it possible to study the behaviour of pacemaker, in vitro, subjected to electromagnetic disturbances in low frequencies range (50 hz - 500 khz). The test bed in which the pacemaker is implanted is described in this article. The process of calculation uses the admittance method adapted to the case of conducted disturbances. Results obtained by numerical simulation are close to experimental values. (authors)

  1. A numerical approach to calculate the induced voltage in the case of conduced perturbations

    International Nuclear Information System (INIS)

    Andretzko, J.P.; Hedjiedj, A.; Babouri, A.; Guendouz, L.; Nadi, M.

    2006-01-01

    This paper presents a method of numerical simulation that makes it possible to calculate the induced tension to the terminals of the cardiac pacemaker subjected to conduced disturbances. The physical model used for simulation is an experimental test bed which makes it possible to study the behaviour of pacemaker, in vitro, subjected to electromagnetic disturbances in low frequencies range (50 hz - 500 khz). The test bed in which the pacemaker is implanted is described in this article. The process of calculation uses the admittance method adapted to the case of conducted disturbances. Results obtained by numerical simulation are close to experimental values. (authors)

  2. Optimization of the Fabrication Route of Ferritic/Martensitic ODS Cladding Tubes: Metallurgical Approach and Pilgering Numerical Modeling

    International Nuclear Information System (INIS)

    Logé, R.E.; Vanegas-Marques, E.; Mocellin, K.; Toualbi, L.; Carlan, Y. de

    2013-01-01

    Conclusions: • Fabrication route of 9Cr-ODS (martensitic) alloys is well controlled. • Fabrication route of 14Cr-ODS (ferritic) should be further optimized. • The choice between a ferritic or a martensitic grade is not already done, it will depend also on the behaviour under irradiation, the corrosion resistance … • Part of the optimization can rely on numerical simulation of pilgering: • The constitutive behaviour is an essential ingredient for process optimization: appropriate cyclic laws must be used. • The numerical analysis can look at cracking risks, final yield stress, and even residual stress state or surface roughness. • HPTR laboratory approaches can be translated to the (industrial) VMR process provided some additional adjustments in the numerical code

  3. A DG approach to the numerical solution of the Stein-Stein stochastic volatility option pricing model

    Science.gov (United States)

    Hozman, J.; Tichý, T.

    2017-12-01

    Stochastic volatility models enable to capture the real world features of the options better than the classical Black-Scholes treatment. Here we focus on pricing of European-style options under the Stein-Stein stochastic volatility model when the option value depends on the time, on the price of the underlying asset and on the volatility as a function of a mean reverting Orstein-Uhlenbeck process. A standard mathematical approach to this model leads to the non-stationary second-order degenerate partial differential equation of two spatial variables completed by the system of boundary and terminal conditions. In order to improve the numerical valuation process for a such pricing equation, we propose a numerical technique based on the discontinuous Galerkin method and the Crank-Nicolson scheme. Finally, reference numerical experiments on real market data illustrate comprehensive empirical findings on options with stochastic volatility.

  4. Ductility Analysis of RC Beams Considering the Concrete Confinement Effect Produced by the Shear Reinforcement: a Numerical Approach

    Directory of Open Access Journals (Sweden)

    Caio Gorla Nogueira

    Full Text Available Abstract In this paper, a simplified numerical approach to study the influence of the confinement effect provided by transversal reinforcement on the ductility behavior of RC beams in bending is proposed. A unidimensional FEM mechanical model coupled to the Mazars’ damage model to simulate concrete behavior was adopted to assess ductility curvatures at the ultimate limit state. The confinement effect was incorporated to the numerical model through a calibration process of the damage internal parameters, based on the Least Square Method and an analytical law proposed by Kent and Park (1971. Several numerical analyses were carried out considering different designs of RC beams according to a parametric study varying the neutral axis position, concrete compressive strength and the volumetric transversal reinforcement ratio. The obtained results showed the importance of the amount of transversal reinforcement on the ductility behavior, increasing the ductility factor even for the cases with inappropriate neutral axis position.

  5. The numerical simulation of heat transfer during a hybrid laser-MIG welding using equivalent heat source approach

    Science.gov (United States)

    Bendaoud, Issam; Matteï, Simone; Cicala, Eugen; Tomashchuk, Iryna; Andrzejewski, Henri; Sallamand, Pierre; Mathieu, Alexandre; Bouchaud, Fréderic

    2014-03-01

    The present study is dedicated to the numerical simulation of an industrial case of hybrid laser-MIG welding of high thickness duplex steel UR2507Cu with Y-shaped chamfer geometry. It consists in simulation of heat transfer phenomena using heat equivalent source approach and implementing in finite element software COMSOL Multiphysics. A numerical exploratory designs method is used to identify the heat sources parameters in order to obtain a minimal required difference between the numerical results and the experiment which are the shape of the welded zone and the temperature evolution in different locations. The obtained results were found in good correspondence with experiment, both for melted zone shape and thermal history.

  6. A Predictor-Corrector Approach for the Numerical Solution of Fractional Differential Equations

    Science.gov (United States)

    Diethelm, Kai; Ford, Neville J.; Freed, Alan D.; Gray, Hugh R. (Technical Monitor)

    2002-01-01

    We discuss an Adams-type predictor-corrector method for the numerical solution of fractional differential equations. The method may be used both for linear and for nonlinear problems, and it may be extended to multi-term equations (involving more than one differential operator) too.

  7. Numerical modeling of large field-induced strains in ferroelastic bodies: a continuum approach

    International Nuclear Information System (INIS)

    Raikher, Yu L; Stolbov, O V

    2008-01-01

    A consistent continuum model of a soft magnetic elastomer (SME) is presented and developed for the case of finite strain. The numeric algorithm enabling one to find the field-induced shape changes of an SME body is described. The reliability of the method is illustrated by several examples revealing specifics of the magnetostriction effect in SME samples of various geometries

  8. Understanding the tensile behaviour of masonry parallel to the bed joints: A numerical approach

    NARCIS (Netherlands)

    Lourenço, P.B.; Rots, J.G.; Pluijm, R. van der

    1999-01-01

    The lack of experimental data for the complete characterisation of the inelastic behaviour of masonry is a key issue in numerical modelling of masonry structures. A solution to obtain the material properties of masonry at the macro-level is to derive them on the basis of the geometrical and material

  9. The numerical-statistical approach for hazard prediction of landslides and its application in Ukraine

    Science.gov (United States)

    Trofimchuk, O.; Kaliukh, Iu.

    2012-04-01

    More than 90% of the territory of Ukraine has complex ground conditions. Unpredictable changes of natural geological and man-made factors governing ground conditions, may lead to dangerous deformation processes resulting in accidents and disasters. Among them, landslides are the first by the amount of the inflicted damage in Ukraine and the second only to earthquakes in the world. Totally about 23 000 landslides were identified in the territory of Ukraine. The standard deterministic procedure of assessment of the slope stability, especially with the lack of reference engineering geological data, results in obtaining estimated values of stability coefficients differing from the real ones in many cases. Application of a probabilistic approach will allow to take into account the changeable properties of soils and to determine danger and risk of landslide dislocations. The matter of choice of landslide protection measures is directly connected with a risk: expensively but reliably or cheaper but with a great probability of accidents. The risk determines the consequences either economic, social or others, of a potential landslide dislocation on the slope both during construction of a retaining structure on it and in the process of its further maintenance. The quintessence of risk determination consists in the following: study and extrapolation of the past events for each specific occurrence. Expected conclusions and probable damages as a result of a calculated and accepted risk can be determined only with a certain level of uncertainty. Considering this fact improvement of the accuracy of numerical and analytical estimates when calculating the risk magnitude makes it possible to reduce the uncertainty. Calculations of the Chernivtsi shear landslides (Ukraine) were made with an application of Plaxis software and due account of a risk of its displacement was performed for the typical distribution diagram of the landslide-prone slope. The calculations showed that seismic

  10. Investigation of eddy currents in the components of the dynamic ergodic divertor of TEXTOR using analytical and numerical approaches

    International Nuclear Information System (INIS)

    Giesen, B.; Neubauer, O.; Bondarchuk, E.; Doinikov, N.; Kitaev, B.; Obidenko, T.; Panin, A.

    2003-01-01

    Analytical and numerical approaches for the calculation of eddy currents in mechanical structures of the TEXTOR tokamak in view of operating the dynamic ergodic divertor (DED) coil system fed with the alternating current up to 15 kA at frequencies up to 10 kHz are described. The design of the in-vessel components located close to the DED coils requires detailed investigation of eddy current effects to avoid unacceptable heating and forces. Different approaches depending on skin-layer depths compared with the body dimensions are analyzed. The applied algorithms are based on analytical and simplified numerical methods. Precision and application range of these algorithms have been checked by a numerical code. The simplified technique is rather effective for first step engineering estimation and gives a good understanding for the problem. In a certain parameter range, it results in even precise values and can be used for design optimization of the structures without huge efforts in numerical modeling. After modification of the component's shape prototypes have been manufactured and successfully tested in a full-scale model under the real DED field. The design recommendations resulting from the eddy current studies contributed significantly to the optimized lay out of the DED in-vessel components

  11. Validation of accuracy and stability of numerical simulation for 2-D heat transfer system by an entropy production approach

    Directory of Open Access Journals (Sweden)

    Brohi Ali Anwar

    2017-01-01

    Full Text Available The entropy production in 2-D heat transfer system has been analyzed systematically by using the finite volume method, to develop new criteria for the numerical simulation in case of multidimensional systems, with the aid of the CFD codes. The steady-state heat conduction problem has been investigated for entropy production, and the entropy production profile has been calculated based upon the current approach. From results for 2-D heat conduction, it can be found that the stability of entropy production profile exhibits a better agreement with the exact solution accordingly, and the current approach is effective for measuring the accuracy and stability of numerical simulations for heat transfer problems.

  12. Specificity of a prodrug-activating enzyme hVACVase: the leaving group effect.

    Science.gov (United States)

    Sun, Jing; Dahan, Arik; Walls, Zachary F; Lai, Longsheng; Lee, Kyung-Dall; Amidon, Gordon L

    2010-12-06

    Human valacyclovirase (hVACVase) is a prodrug-activating enzyme for amino acid prodrugs including the antiviral drugs valacyclovir and valganciclovir. In hVACVase-catalyzed reactions, the leaving group of the substrate corresponds to the drug moiety of the prodrug, making the leaving group effect essential for the rational design of new prodrugs targeting hVACVase activation. In this study, a series of valine esters, phenylalanine esters, and a valine amide were characterized for the effect of the leaving group on the efficiency of hVACVase-mediated prodrug activation. Except for phenylalanine methyl and ethyl esters, all of the ester substrates exhibited a relatively high specificity constant (k(cat)/K(m)), ranging from 850 to 9490 mM(-1)·s(-1). The valine amide Val-3-APG exhibited significantly higher K(m) and lower k(cat) values compared to the corresponding ester Val-3-HPG, indicating poor specificity for hVACVase. In conclusion, the substrate leaving group has been shown to affect both binding and specific activity of hVACVase-catalyzed activation. It is proposed that hVACVase is an ideal target for α-amino acid ester prodrugs with relatively labile leaving groups while it is relatively inactivate toward amide prodrugs.

  13. Development of generalized boiling transition model applicable for wide variety of fuel bundle geometries. Basic strategy and numerical approaches

    International Nuclear Information System (INIS)

    Ninokata, Hisashi; Sadatomi, Michio; Okawa, Tomio

    2003-01-01

    In order to establish a key technology to realize advanced BWR fuel designs, a three-year project of the advanced subchannel analysis code development had been started since 2002. The five dominant factors involved in the boiling transitional process in the fuel bundles were focused. They are, (1) inter-subchannel exchanges, (2) influences of obstacles (3) dryout of liquid film, (4) transition of two-phase flow regimes and (5) deposition of droplets. It has been recognized that present physical models or constitutive equations in subchannel formulations need to be improved so that they include geometrical effects in the fuel bundle design more mechanistically and universally. Through reviewing literatures and existent experimental results, underlying elementary processes and geometrical factors that are indispensable for improving subchannel codes were identified. The basic strategy that combines numerical and experimental approaches was proposed aiming at establishment of mechanistic models for the five dominant factors. In this paper, the present status of methodologies for detailed two-phase flow studies has been summarized. According to spatial scales of focused elementary processes, proper numerical approaches were selected. For some promising numerical approaches, preliminary calcitonins were performed for assessing their applicability to investigation of elementary processes involved in the boiling transition. (author)

  14. Numerical approach for optimum electromagnetic parameters of electrical machines used in vehicle traction applications

    International Nuclear Information System (INIS)

    Fodorean, D.; Giurgea, S.; Djerdir, A.; Miraoui, A.

    2009-01-01

    A large speed variation is an essential request in the automobile industry. In order to compete with diesel engines, the flux weakening technique has to be employed on the electrical machines. In this way, appropriate electromagnetic and geometrical parameters can give the desired speed. Using the inverse problem method coupled with numerical analysis by finite element method (FEM), the authors propose an optimum parameters configuration that maximizes the speed domain operation. Several types of electrical machines are under study: induction, synchronous permanent magnet, variable reluctance and transverse flux machines, respectively. With a proper non-linear model, by using analytical and numerical calculation, the authors propose an optimum solution for the speed variation of the studied drives, which will be standing for a final comparison.

  15. A Numerical-Analytical Approach Based on Canonical Transformations for Computing Optimal Low-Thrust Transfers

    Science.gov (United States)

    da Silva Fernandes, S.; das Chagas Carvalho, F.; Bateli Romão, J. V.

    2018-04-01

    A numerical-analytical procedure based on infinitesimal canonical transformations is developed for computing optimal time-fixed low-thrust limited power transfers (no rendezvous) between coplanar orbits with small eccentricities in an inverse-square force field. The optimization problem is formulated as a Mayer problem with a set of non-singular orbital elements as state variables. Second order terms in eccentricity are considered in the development of the maximum Hamiltonian describing the optimal trajectories. The two-point boundary value problem of going from an initial orbit to a final orbit is solved by means of a two-stage Newton-Raphson algorithm which uses an infinitesimal canonical transformation. Numerical results are presented for some transfers between circular orbits with moderate radius ratio, including a preliminary analysis of Earth-Mars and Earth-Venus missions.

  16. Numerical simulation of nonequilibrium flows by using the state-to-state approach in commercial software

    Science.gov (United States)

    Kunova, O. V.; Shoev, G. V.; Kudryavtsev, A. N.

    2017-01-01

    Nonequilibrium flows of a two-component oxygen mixture O2/O behind a shock wave are studied with due allowance for the state-to-state vibrational and chemical kinetics. The system of gas-dynamic equations is supplemented with kinetic equations including contributions of VT (TV)-exchange and dissociation processes. A method of the numerical solution of this system with the use of the ANSYS Fluent commercial software package is proposed, which is used in a combination with the authors' code that takes into account nonequilibrium kinetics. The computed results are compared with parameters obtained by solving the problem in the shock-fitting formulation. The vibrational temperature is compared with experimental data. The numerical tool proposed in the present paper is applied to study the flow around a cylinder.

  17. Numerical approach to optimal portfolio in a power utility regime-switching model

    Science.gov (United States)

    Gyulov, Tihomir B.; Koleva, Miglena N.; Vulkov, Lubin G.

    2017-12-01

    We consider a system of weakly coupled degenerate semi-linear parabolic equations of optimal portfolio in a regime-switching with power utility function, derived by A.R. Valdez and T. Vargiolu [14]. First, we discuss some basic properties of the solution of this system. Then, we develop and analyze implicit-explicit, flux limited finite difference schemes for the differential problem. Numerical experiments are discussed.

  18. Numerical approach for quantification of self wastage phenomena in sodium-cooled fast reactor

    International Nuclear Information System (INIS)

    Jang, Sung Hyun; Takata, Takashi; Yamaguchi, Akira; Uchbori, Akihiro; Kurihara, Akikazu; Ohshima, Hiroyuki

    2015-01-01

    Sodium-cooled fast breeder reactors use liquid sodium as a moderator and coolant to transfer heat from the reactor core. The main hazard associated with sodium is its rapid reaction with water. Sodium-water reaction (SWR) takes place when water or vapor leak into the sodium side through a crack on a heat-transfer tube in a steam generator. If the SWR continues for some time, the SWR will damage the surface of the defective area, causing it to enlarge. This self-enlargement of the crack is called 'self-wastage phenomena'. A stepwise numerical evaluation model of the self-wastage phenomena was devised using a computational code of multicomponent multiphase flow involving a sodium-water chemical reaction: sodium-water reaction analysis physics of interdisciplinary multiphase flow (SERAPHIM). The temperature of gas mixture and the concentration of NaOH at the surface of the tube wall are obtained by a numerical calculation using SERAPHIM. Averaged thermophysical properties are used to assess the local wastage depth at the tube surface. By reflecting the wastage depth to the computational grid, the self-wastage phenomena are evaluated. A two-dimensional benchmark analysis of an SWAT (Sodium-Water reAction Test rig) experiment is carried out to evaluate the feasibility of the numerical model. Numerical results show that the geometry and scale of enlarged cracks show good agreement with the experimental result. Enlarged cracks appear to taper inward to a significantly smaller opening on the inside of the tube wall. The enlarged outer diameter of the crack is 4.72 mm, which shows good agreement with the experimental data (4.96 mm)

  19. Circles in the spectrum and the geometry of orbits: a numerical ranges approach

    Czech Academy of Sciences Publication Activity Database

    Müller, Vladimír; Tomilov, Y.

    2018-01-01

    Roč. 274, č. 2 (2018), s. 433-460 ISSN 0022-1236 R&D Projects: GA ČR(CZ) GA14-07880S EU Projects: European Commission(XE) 318910 - AOS Institutional support: RVO:67985840 Keywords : spectrum * orbits of linear operators * numerical range * convergence of operator iterates Subject RIV: BA - General Mathematics OBOR OECD: Pure mathematics Impact factor: 1.254, year: 2016 http://www.sciencedirect.com/science/article/pii/S0022123617304111?via%3Dihub

  20. An efficient approach to the numerical solution of rate-independent problems with nonconvex energies

    Czech Academy of Sciences Publication Activity Database

    Bartels, S.; Kružík, Martin

    2011-01-01

    Roč. 9, č. 3 (2011), s. 1275-1300 ISSN 1540-3459 R&D Projects: GA AV ČR IAA100750802 Grant - others:GA ČR(CZ) GAP201/10/0357 Institutional research plan: CEZ:AV0Z10750506 Keywords : numerical solution * nonconvexity Subject RIV: BA - General Mathematics Impact factor: 2.009, year: 2011 http://library.utia.cas.cz/separaty/2011/MTR/kruzik-0364707.pdf

  1. Numerical modeling of flow processes inside geothermal wells: An approach for predicting production characteristics with uncertainties

    Energy Technology Data Exchange (ETDEWEB)

    Garcia-Valladares, O.; Santoyo, E. [Centro de Investigacion en Energia (UNAM), Privada Xochicalco s/n, Temixco, Mor. 62580 (Mexico); Sanchez-Upton, P. [Posgrado en Ingenieria (Energia), UNAM, Privada Xochicalco s/n, Temixco, Mor. 62580 (Mexico)

    2006-07-15

    One dimensional steady and transient numerical modeling for describing the heat and fluid dynamic transport inside geothermal wells has been conducted. The mass, momentum and energy governing equations were solved using a segregated numerical scheme. Discretized governing equations for the fluid flow were coupled and solved with a fully implicit step by step method. The mathematical formulation used suitable empirical correlations for estimating the convective heat transfer coefficients as well as the shear stress and the void fraction parameters. Heat conduction across the wellbore materials was solved by an implicit central difference numerical scheme using the tri-diagonal matrix algorithm (TDMA). The flow characteristics of producer geothermal wells (pressure, temperature, enthalpy, heat fluxes, etc.) at each depth node were computed. Analytical data reported in the literature were used to validate the numerical capability of the wellbore simulator developed for this study (GEOWELLS). This simulator, together with another computer code (ORKISZEWSKI), was applied for modeling the heat and fluid flow processes inside some wells drilled in Mexican geothermal fields. The simulated pressure and temperature profiles were statistically compared against stable measured field data (through the computation of the residual sum of squares and Chi-square). A good agreement between the simulated and measured profiles of pressure and temperature was consistently obtained, having the best matching results for the GEOWELLS predictions. An analysis of the sensitivity and uncertainty was finally conducted to estimate the confidence to be accorded the simulation results predicted by GEOWELLS. Matching the sensitivity to variations in some input parameters (e.g., pressure, temperature, enthalpy and void fraction) was examined. The void fraction was identified as one of the most important parameters that affect the GEOWELLS simulations for matching measured field data correctly

  2. Numerical modeling of flow processes inside geothermal wells: An approach for predicting production characteristics with uncertainties

    International Nuclear Information System (INIS)

    Garcia-Valladares, O.; Sanchez-Upton, P.; Santoyo, E.

    2006-01-01

    One dimensional steady and transient numerical modeling for describing the heat and fluid dynamic transport inside geothermal wells has been conducted. The mass, momentum and energy governing equations were solved using a segregated numerical scheme. Discretized governing equations for the fluid flow were coupled and solved with a fully implicit step by step method. The mathematical formulation used suitable empirical correlations for estimating the convective heat transfer coefficients as well as the shear stress and the void fraction parameters. Heat conduction across the wellbore materials was solved by an implicit central difference numerical scheme using the tri-diagonal matrix algorithm (TDMA). The flow characteristics of producer geothermal wells (pressure, temperature, enthalpy, heat fluxes, etc.) at each depth node were computed. Analytical data reported in the literature were used to validate the numerical capability of the wellbore simulator developed for this study (GEOWELLS). This simulator, together with another computer code (ORKISZEWSKI), was applied for modeling the heat and fluid flow processes inside some wells drilled in Mexican geothermal fields. The simulated pressure and temperature profiles were statistically compared against stable measured field data (through the computation of the residual sum of squares and Chi-square). A good agreement between the simulated and measured profiles of pressure and temperature was consistently obtained, having the best matching results for the GEOWELLS predictions. An analysis of the sensitivity and uncertainty was finally conducted to estimate the confidence to be accorded the simulation results predicted by GEOWELLS. Matching the sensitivity to variations in some input parameters (e.g., pressure, temperature, enthalpy and void fraction) was examined. The void fraction was identified as one of the most important parameters that affect the GEOWELLS simulations for matching measured field data correctly

  3. Numerical approach for quantification of self wastage phenomena in sodium-cooled fast reactor

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Sung Hyun; Takata, Takashi [Graduate School of Engineering, Osaka University, Osaka (Japan); Yamaguchi, Akira [Graduate School of Engineering, The University of Tokyo, Ibaraki (Japan); Uchbori, Akihiro; Kurihara, Akikazu; Ohshima, Hiroyuki [Japan Atomic Energy Agency, Ibaraki (Japan)

    2015-10-15

    Sodium-cooled fast breeder reactors use liquid sodium as a moderator and coolant to transfer heat from the reactor core. The main hazard associated with sodium is its rapid reaction with water. Sodium-water reaction (SWR) takes place when water or vapor leak into the sodium side through a crack on a heat-transfer tube in a steam generator. If the SWR continues for some time, the SWR will damage the surface of the defective area, causing it to enlarge. This self-enlargement of the crack is called 'self-wastage phenomena'. A stepwise numerical evaluation model of the self-wastage phenomena was devised using a computational code of multicomponent multiphase flow involving a sodium-water chemical reaction: sodium-water reaction analysis physics of interdisciplinary multiphase flow (SERAPHIM). The temperature of gas mixture and the concentration of NaOH at the surface of the tube wall are obtained by a numerical calculation using SERAPHIM. Averaged thermophysical properties are used to assess the local wastage depth at the tube surface. By reflecting the wastage depth to the computational grid, the self-wastage phenomena are evaluated. A two-dimensional benchmark analysis of an SWAT (Sodium-Water reAction Test rig) experiment is carried out to evaluate the feasibility of the numerical model. Numerical results show that the geometry and scale of enlarged cracks show good agreement with the experimental result. Enlarged cracks appear to taper inward to a significantly smaller opening on the inside of the tube wall. The enlarged outer diameter of the crack is 4.72 mm, which shows good agreement with the experimental data (4.96 mm)

  4. Composite magnetic refrigerants for an Ericsson cycle: New method of selection using a numerical approach

    International Nuclear Information System (INIS)

    Smaieli, A.; Chahine, R.

    1997-01-01

    The efficient operation of an Ericsson cycle requires the magnetic entropy change (AS) be constant as a function of temperature. To realize this condition using composite materials, a numerical method has been developed to determine the optimum proportions of the components. The Gd x Er 1-x (x = 0.69, 0.90) alloys have been used to investigate the validity of the numerical method. The values of ΔS have been determined from experimental magnetization curves of these alloys, in the 0.1-9 T magnetic field and the 200-290 K range. The calculations have led to the mass ratio y = 0.56 for the composite (Gd 0.90 Er 0.10 ) y (Gd 0.69 Er 0.31 ) 1-y . The ΔS of this composite is fairly constant in the 225-280 K range. To confirm this result, the magnetization curves of the composite material have been determined experimentally, and the corresponding ΔS was compared with the one predicted numerically. A good agreement was found proving the method's ability to properly determine the required fractions of the refrigerant's constituent materials

  5. An approach to first principles electronic structure calculation by symbolic-numeric computation

    Directory of Open Access Journals (Sweden)

    Akihito Kikuchi

    2013-04-01

    Full Text Available There is a wide variety of electronic structure calculation cooperating with symbolic computation. The main purpose of the latter is to play an auxiliary role (but not without importance to the former. In the field of quantum physics [1-9], researchers sometimes have to handle complicated mathematical expressions, whose derivation seems almost beyond human power. Thus one resorts to the intensive use of computers, namely, symbolic computation [10-16]. Examples of this can be seen in various topics: atomic energy levels, molecular dynamics, molecular energy and spectra, collision and scattering, lattice spin models and so on [16]. How to obtain molecular integrals analytically or how to manipulate complex formulas in many body interactions, is one such problem. In the former, when one uses special atomic basis for a specific purpose, to express the integrals by the combination of already known analytic functions, may sometimes be very difficult. In the latter, one must rearrange a number of creation and annihilation operators in a suitable order and calculate the analytical expectation value. It is usual that a quantitative and massive computation follows a symbolic one; for the convenience of the numerical computation, it is necessary to reduce a complicated analytic expression into a tractable and computable form. This is the main motive for the introduction of the symbolic computation as a forerunner of the numerical one and their collaboration has won considerable successes. The present work should be classified as one such trial. Meanwhile, the use of symbolic computation in the present work is not limited to indirect and auxiliary part to the numerical computation. The present work can be applicable to a direct and quantitative estimation of the electronic structure, skipping conventional computational methods.

  6. Kinetic approach in numerical modeling of melting and crystallization at laser cladding with powder injection

    Energy Technology Data Exchange (ETDEWEB)

    Mirzade, F. Kh., E-mail: fmirzade@rambler.ru [Institute on Laser and Information Technology, Russian Academy of Sciences, 1 Svyatoozerskaya Street, Shatura, Moscow Region 140700 (Russian Federation); Niziev, V.G.; Panchenko, V. Ya.; Khomenko, M.D.; Grishaev, R.V. [Institute on Laser and Information Technology, Russian Academy of Sciences, 1 Svyatoozerskaya Street, Shatura, Moscow Region 140700 (Russian Federation); Pityana, S.; Rooyen, Corney van [CSIR-National Laser Centre, Building 46A, Meiring Nauder Road, Brummeria, Pretoria (South Africa)

    2013-08-15

    The numerical model of laser cladding with coaxial powder injection includes the equations for heat transfer, melting and crystallization kinetics. It has been shown that the main parameters influencing the melt pool dynamics and medium maximum temperature are mass feed rate, laser power and scanning velocity. It has been observed that, due to the phase change occurring with superheating/undercooling, the melt zone has the boundary distinguished from melting isotherm. The calculated melt pool dimensions and dilution are in a good agreement with the experimental results for cladding of 431 martensitic stainless steel onto carbon steel substrate.

  7. Circles in the spectrum and the geometry of orbits: a numerical ranges approach

    Czech Academy of Sciences Publication Activity Database

    Müller, Vladimír; Tomilov, Y.

    2018-01-01

    Roč. 274, č. 2 (2018), s. 433-460 ISSN 0022-1236 R&D Projects: GA ČR(CZ) GA14-07880S EU Projects: European Commission(XE) 318910 - AOS Institutional support: RVO:67985840 Keywords : spectrum * orbits of linear operators * numerical range * convergence of operator iterates Subject RIV: BA - General Mathematics OBOR OECD: Pure mathematics Impact factor: 1.254, year: 2016 http://www. science direct.com/ science /article/pii/S0022123617304111?via%3Dihub

  8. Risk management for existing energy facilities. A global approach to numerical safety goals

    International Nuclear Information System (INIS)

    Pate-Cornell, M.E.

    1993-01-01

    This paper presents a structured set of numerical safety goals for risk management of existing energy facilities. The rationale behind these safety goals is based on principles of equity and economic efficiency. Some of the issues involved when using probabilistic risk analyses results for safety decisions are discussed. A brief review of existing safety targets and open-quotes floating numbersclose quotes is presented, and a set of safety goals for industrial risk management is proposed. Relaxation of these standards for existing facilities, the relevance of the lifetime of the plant, the treatment of uncertainties, and problems of failure dependencies are discussed briefly. 17 refs., 1 fig

  9. An equivalent fluid/equivalent medium approach for the numerical simulation of coastal landslides propagation: theory and case studies

    Directory of Open Access Journals (Sweden)

    P. Mazzanti

    2009-11-01

    Full Text Available Coastal and subaqueous landslides can be very dangerous phenomena since they are characterised by the additional risk of induced tsunamis, unlike their completely-subaerial counterparts. Numerical modelling of landslides propagation is a key step in forecasting the consequences of landslides. In this paper, a novel approach named Equivalent Fluid/Equivalent Medium (EFEM has been developed. It adapts common numerical models and software that were originally designed for subaerial landslides in order to simulate the propagation of combined subaerial-subaqueous and completely-subaqueous landslides. Drag and buoyancy forces, the loss of energy at the landslide-water impact and peculiar mechanisms like hydroplaning can be suitably simulated by this approach; furthermore, the change in properties of the landslide's mass, which is encountered at the transition from the subaerial to the submerged environment, can be taken into account. The approach has been tested by modelling two documented coastal landslides (a debris flow and a rock slide at Lake Albano using the DAN-W code. The results, which were achieved from the back-analyses, demonstrate the efficacy of the approach to simulate the propagation of different types of coastal landslides.

  10. A model reduction approach to numerical inversion for a parabolic partial differential equation

    International Nuclear Information System (INIS)

    Borcea, Liliana; Druskin, Vladimir; Zaslavsky, Mikhail; Mamonov, Alexander V

    2014-01-01

    We propose a novel numerical inversion algorithm for the coefficients of parabolic partial differential equations, based on model reduction. The study is motivated by the application of controlled source electromagnetic exploration, where the unknown is the subsurface electrical resistivity and the data are time resolved surface measurements of the magnetic field. The algorithm presented in this paper considers inversion in one and two dimensions. The reduced model is obtained with rational interpolation in the frequency (Laplace) domain and a rational Krylov subspace projection method. It amounts to a nonlinear mapping from the function space of the unknown resistivity to the small dimensional space of the parameters of the reduced model. We use this mapping as a nonlinear preconditioner for the Gauss–Newton iterative solution of the inverse problem. The advantage of the inversion algorithm is twofold. First, the nonlinear preconditioner resolves most of the nonlinearity of the problem. Thus the iterations are less likely to get stuck in local minima and the convergence is fast. Second, the inversion is computationally efficient because it avoids repeated accurate simulations of the time-domain response. We study the stability of the inversion algorithm for various rational Krylov subspaces, and assess its performance with numerical experiments. (paper)

  11. A model reduction approach to numerical inversion for a parabolic partial differential equation

    Science.gov (United States)

    Borcea, Liliana; Druskin, Vladimir; Mamonov, Alexander V.; Zaslavsky, Mikhail

    2014-12-01

    We propose a novel numerical inversion algorithm for the coefficients of parabolic partial differential equations, based on model reduction. The study is motivated by the application of controlled source electromagnetic exploration, where the unknown is the subsurface electrical resistivity and the data are time resolved surface measurements of the magnetic field. The algorithm presented in this paper considers inversion in one and two dimensions. The reduced model is obtained with rational interpolation in the frequency (Laplace) domain and a rational Krylov subspace projection method. It amounts to a nonlinear mapping from the function space of the unknown resistivity to the small dimensional space of the parameters of the reduced model. We use this mapping as a nonlinear preconditioner for the Gauss-Newton iterative solution of the inverse problem. The advantage of the inversion algorithm is twofold. First, the nonlinear preconditioner resolves most of the nonlinearity of the problem. Thus the iterations are less likely to get stuck in local minima and the convergence is fast. Second, the inversion is computationally efficient because it avoids repeated accurate simulations of the time-domain response. We study the stability of the inversion algorithm for various rational Krylov subspaces, and assess its performance with numerical experiments.

  12. Internal modifications to reduce pollutant emissions from marine engines. A numerical approach

    Science.gov (United States)

    Lamas, M. I.; Rodríguez, C. G.; Rodríguez, J. D.; Telmo, J.

    2013-12-01

    Taking into account the increasingly stringent legislation on emissions from marine engines, this work aims to analyze several internal engine modifications to reduce NOx (nitrogen oxides) and other pollutants. To this end, a numerical model was employed to simulate the operation cycle and characterize the exhaust gas composition. After a preliminary validation process was carried out using experimental data from a four-stroke, medium-speed marine engine, the numerical model was employed to study the influence of several internal modifications, such as water addition from 0 to 100% water to fuel ratios, exhaust gas recirculation from 0 to 100% EGR rates, modification of the overlap timing from 60 to 120°, modification of the intake valve closing from 510 to 570°, and modification of the cooling water temperature from 70 to 90 oC. NOx was reduced by nearly 100%. As expected, it was found that, by lowering the combustion temperature, there is a notable reduction in NOx, but an increase in CO (carbon monoxide), HC (hydrocarbons) and consumption.

  13. Internal modifications to reduce pollutant emissions from marine engines. A numerical approach

    Directory of Open Access Journals (Sweden)

    M.I. Lamas

    2013-12-01

    Full Text Available Taking into account the increasingly stringent legislation on emissions from marine engines, this work aims to analyze several internal engine modifications to reduce NOx (nitrogen oxides and other pollutants. To this end, a numerical model was employed to simulate the operation cycle and characterize the exhaust gas composition. After a preliminary validation process was carried out using experimental data from a four-stroke, medium-speed marine engine, the numerical model was employed to study the influence of several internal modifications, such as water addition from 0 to 100% water to fuel ratios, exhaust gas recirculation from 0 to 100% EGR rates, modification of the overlap timing from 60 to 120°, modification of the intake valve closing from 510 to 570°, and modification of the cooling water temperature from 70 to 90 °C. NOx was reduced by nearly 100%. As expected, it was found that, by lowering the combustion temperature, there is a notable reduction in NOx, but an increase in CO (carbon monoxide, HC (hydrocarbons and consumption.

  14. Kidney damage in extracorporeal shock wave lithotripsy: a numerical approach for different shock profiles.

    Science.gov (United States)

    Weinberg, Kerstin; Ortiz, Michael

    2009-08-01

    In shock-wave lithotripsy--a medical procedure to fragment kidney stones--the patient is subjected to hypersonic waves focused at the kidney stone. Although this procedure is widely applied, the physics behind this medical treatment, in particular the question of how the injuries to the surrounding kidney tissue arise, is still under investigation. To contribute to the solution of this problem, two- and three-dimensional numerical simulations of a human kidney under shock-wave loading are presented. For this purpose a constitutive model of the bio-mechanical system kidney is introduced, which is able to map large visco-elastic deformations and, in particular, material damage. The specific phenomena of cavitation induced oscillating bubbles is modeled here as an evolution of spherical pores within the soft kidney tissue. By means of large scale finite element simulations, we study the shock-wave propagation into the kidney tissue, adapt unknown material parameters and analyze the resulting stress states. The simulations predict localized damage in the human kidney in the same regions as observed in animal experiments. Furthermore, the numerical results suggest that in first instance the pressure amplitude of the shock wave impulse (and not so much its exact time-pressure profile) is responsible for damaging the kidney tissue.

  15. A numerical approach to the time dependent neutron flux using the Laplace transform technique

    International Nuclear Information System (INIS)

    El-Demerdash, A; Beynon, T.D.

    1979-01-01

    In this study a time dependent transport problem in which an isotopic neutron source emits a pulse of neutrons into a finite sphere has been solved by a numerical Laplace transform technique. The object has been to investigate the time behaviour of the neutron field in the moderators at times shortly after the neutron source initiation, that is in the nanosecond time period. The basis of the solution is a numercial evaluation of the Laplace transform of the flux in the linear Boltzmann equation with the use of a modified version of a steady state energy multi-group spatially dependent code. The explicit or direct inversion of the Laplace transformed flux is complicated to be solved numerically due to the ill-conditioned matrix obtained. The suggested method of solutions depends on choice of a function that satisfies the physical condition known from the neutron behaviour and that has a Laplace inversion which is analytically amenable. By employing a least square fitting procedure the function is modified in order to minimize the error in the Laplace transformed values and hence in the time dependent solution. This method has been applied satisfactorily in comparison to analytical and experimental results

  16. Pattern formation and filamentation in low temperature, magnetized plasmas - a numerical approach

    Science.gov (United States)

    Menati, Mohamad; Konopka, Uwe; Thomas, Edward

    2017-10-01

    In low-temperature discharges under the influence of high magnetic field, pattern and filament formation in the plasma has been reported by different groups. The phenomena present themselves as bright plasma columns (filaments) oriented parallel to the magnetic field lines at high magnetic field regime. The plasma structure can filament into different shapes from single columns to spiral and bright rings when viewed from the top. In spite of the extensive experimental observations, the observed effects lack a detailed theoretical and numerical description. In an attempt to numerically explain the plasma filamentation, we present a simplified model for the plasma discharge and power deposition into the plasma. Based on the model, 2-D and 3-D codes are being developed that solve Poisson's equation along with the fluid equations to obtain a self-consistent description of the plasma. The model and preliminary results applied to the specific plasma conditions will be presented. This work was supported by the US Dept. of Energy and NSF, DE-SC0016330, PHY-1613087.

  17. Human glutathione transferases catalyzing the bioactivation of anticancer thiopurine prodrugs.

    Science.gov (United States)

    Eklund, Birgitta I; Gunnarsdottir, Sjofn; Elfarra, Adnan A; Mannervik, Bengt

    2007-06-01

    cis-6-(2-Acetylvinylthio)purine (cAVTP) and trans-6-(2-acetylvinylthio)guanine (tAVTG) are thiopurine prodrugs provisionally inactivated by an alpha,beta-unsaturated substituent on the sulfur of the parental thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). The active thiopurines are liberated intracellularly by glutathione (GSH) in reactions catalyzed by glutathione transferases (GSTs) (EC 2.5.1.18). Catalytic activities of 13 human GSTs representing seven distinct classes of soluble GSTs have been determined. The bioactivation of cAVTP and tAVTG occurs via a transient addition of GSH to the activated double bond of the S-substituent of the prodrug, followed by elimination of the thiopurine. The first of these consecutive reactions is rate-limiting for thiopurine release, but GST-activation of this first addition is shifting the rate limitation to the subsequent elimination. Highly active GSTs reveal the transient intermediate, which is detectable by UV spectroscopy and HPLC analysis. LC/MS analysis of the reaction products demonstrates that the primary GSH conjugate, 4-glutathionylbuten-2-one, can react with a second GSH molecule to form the 4-(bis-glutathionyl)butan-2-one. GST M1-1 and GST A4-4 were the most efficient enzymes with tAVTG, and GST M1-1 and GST M2-2 had highest activity with cAVTP. The highly efficient GST M1-1 is polymorphic and is absent in approximately half of the human population. GST P1-1, which is overexpressed in many cancer cells, had no detectable activity with cAVTP and only minor activity with tAVTG. Other GST-activated prodrugs have targeted GST P1-1-expressing cancer cells. Tumors expressing high levels of GST M1-1 or GST A4-4 can be predicted to be particularly vulnerable to chemotherapy with cAVTP or tAVTG.

  18. Nonlinear approaches in engineering applications applied mechanics, vibration control, and numerical analysis

    CERN Document Server

    Jazar, Reza

    2015-01-01

    This book focuses on the latest applications of nonlinear approaches in different disciplines of engineering. For each selected topic, detailed concept development, derivations, and relevant knowledge are provided for the convenience of the readers. The topics range from dynamic systems and control to optimal approaches in nonlinear dynamics. The volume includes invited chapters from world class experts in the field. The selected topics are of great interest in the fields of engineering and physics and this book is ideal for engineers and researchers working in a broad range of practical topics and approaches. This book also: ·         Explores the most up-to-date applications and underlying principles of nonlinear approaches to problems in engineering and physics, including sections on analytic nonlinearity and practical nonlinearity ·         Enlightens readers to the conceptual significance of nonlinear approaches with examples of applications in scientific and engineering problems from v...

  19. Numerical modeling of axi-symmetrical cold forging process by ``Pseudo Inverse Approach''

    Science.gov (United States)

    Halouani, A.; Li, Y. M.; Abbes, B.; Guo, Y. Q.

    2011-05-01

    The incremental approach is widely used for the forging process modeling, it gives good strain and stress estimation, but it is time consuming. A fast Inverse Approach (IA) has been developed for the axi-symmetric cold forging modeling [1-2]. This approach exploits maximum the knowledge of the final part's shape and the assumptions of proportional loading and simplified tool actions make the IA simulation very fast. The IA is proved very useful for the tool design and optimization because of its rapidity and good strain estimation. However, the assumptions mentioned above cannot provide good stress estimation because of neglecting the loading history. A new approach called "Pseudo Inverse Approach" (PIA) was proposed by Batoz, Guo et al.. [3] for the sheet forming modeling, which keeps the IA's advantages but gives good stress estimation by taking into consideration the loading history. Our aim is to adapt the PIA for the cold forging modeling in this paper. The main developments in PIA are resumed as follows: A few intermediate configurations are generated for the given tools' positions to consider the deformation history; the strain increment is calculated by the inverse method between the previous and actual configurations. An incremental algorithm of the plastic integration is used in PIA instead of the total constitutive law used in the IA. An example is used to show the effectiveness and limitations of the PIA for the cold forging process modeling.

  20. Numerical Simulation of a Novel Sensing Approach Based on Abnormal Blocking by Periodic Grating Strips near the Silicon Wire Waveguide

    Directory of Open Access Journals (Sweden)

    Andrei Tsarev

    2018-05-01

    Full Text Available This paper discusses the physical nature and the numerical modeling of a novel approach of periodic structures for applications as photonic sensors. The sensing is based on the high sensitivity to the cover index change of the notch wavelength. This sensitivity is due to the effect of abnormal blocking of the guided wave propagating along the silicon wire with periodic strips overhead it through the silica buffer. The structure sensing is numerically modeled by 2D and 3D finite difference time domain (FDTD method, taking into account the waveguide dispersion. The modeling of the long structures (more than 1000 strips is accomplished by the 2D method of lines (MoL with a maximal implementation of the analytical feature of the method. It is proved that the effect of abnormal blocking could be used for the construction of novel types of optical sensors.

  1. Mouse Mammary Tumor Virus Promoter-Containing Retroviral Promoter Conversion Vectors for Gene-Directed Enzyme Prodrug Therapy are Functional in Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Reinhard Klein

    2008-01-01

    Full Text Available Gene directed-enzyme prodrug therapy (GDEPT is an approach for sensitization of tumor cells to an enzymatically activated, otherwise nontoxic, prodrug. Cytochrome P450 2B1 (CYP2B1 metabolizes the prodrugs cyclophosphamide (CPA and ifosfamide (IFA to produce the cytotoxic substances phosphoramide mustard and isophosphoramide mustard as well as the byproduct acrolein. We have constructed a retroviral promoter conversion (ProCon vector for breast cancer GDEPT. The vector allows expression of CYP2B1 from the mouse mammary tumor virus (MMTV promoter known to be active in the mammary glands of transgenic animals. It is anticipated to be used for the generation of encapsulated viral vector producing cells which, when placed inside or close to a tumor, will act as suppliers of the therapeutic CYP2B1 protein as well as of the therapeutic vector itself. The generated vector was effectively packaged by virus producing cells and allowed the production of high levels of enzymatically active CYP2B1 in infected cells which sensitized them to killing upon treatment with both IFA and CPA. Determination of the respective IC50 values demonstrated that the effective IFA dose was reduced by sixteen folds. Infection efficiencies in vivo were determined using a reporter gene-bearing vector in a mammary cancer cell-derived xenograft tumor mouse model.

  2. How to integrate divergent integrals: a pure numerical approach to complex loop calculations

    International Nuclear Information System (INIS)

    Caravaglios, F.

    2000-01-01

    Loop calculations involve the evaluation of divergent integrals. Usually [G. 't Hooft, M. Veltman, Nucl. Phys. B 44 (1972) 189] one computes them in a number of dimensions different than four where the integral is convergent and then one performs the analytical continuation and considers the Laurent expansion in powers of ε=n-4. In this paper we discuss a method to extract directly all coefficients of this expansion by means of concrete and well defined integrals in a five-dimensional space. We by-pass the formal and symbolic procedure of analytic continuation; instead we can numerically compute the integrals to extract directly both the coefficient of the pole 1/ε and the finite part

  3. A NOVEL NUMERICAL MODEL APPROACH FOR EXAMINING SHIP BERTHING IMPACT ON FLOATING PIERS

    Directory of Open Access Journals (Sweden)

    AMIN CHEGENIZADEH

    2015-08-01

    Full Text Available This paper presents the results of an investigation into the impact of ship berthing upon floating piers using highly advanced numerical software Abaqus. The ship and floating piers were modeled as solid bodies. For the first time, the effect of soil on the total energy absorption of the system was considered using both elastic and elastic-perfectly plastic soil models. First the results for the elastic soil model were compared to and verified by the existing literature using a spring soil model.Then a continuum soil model was utilized instead of a spring soil model, with the results showing 27% higher energy absorption compared to the spring model. The investigation also considered a model with soil as an elastic-perfectly plastic material, being more aligned with the soil material’s real behavior. With this model the results produced 1% more energy absorption as the soil did not reach plastic failure.

  4. Cohesive Laws and Progressive Damage Analysis of Composite Bonded Joints, a Combined Numerical/Experimental Approach

    Science.gov (United States)

    Girolamo, Donato; Davila, Carlos G.; Leone, Frank A.; Lin, Shih-Yung

    2015-01-01

    The results of an experimental/numerical campaign aimed to develop progressive damage analysis (PDA) tools for predicting the strength of a composite bonded joint under tensile loads are presented. The PDA is based on continuum damage mechanics (CDM) to account for intralaminar damage, and cohesive laws to account for interlaminar and adhesive damage. The adhesive response is characterized using standard fracture specimens and digital image correlation (DIC). The displacement fields measured by DIC are used to calculate the J-integrals, from which the associated cohesive laws of the structural adhesive can be derived. A finite element model of a sandwich conventional splice joint (CSJ) under tensile loads was developed. The simulations, in agreement with experimental tests, indicate that the model is capable of predicting the interactions of damage modes that lead to the failure of the joint.

  5. Extremum-Seeking Control and Applications A Numerical Optimization-Based Approach

    CERN Document Server

    Zhang, Chunlei

    2012-01-01

    Extremum seeking control tracks a varying maximum or minimum in a performance function such as a cost. It attempts to determine the optimal performance of a control system as it operates, thereby reducing downtime and the need for system analysis. Extremum Seeking Control and Applications is divided into two parts. In the first, the authors review existing analog optimization based extremum seeking control including gradient, perturbation and sliding mode based control designs. They then propose a novel numerical optimization based extremum seeking control based on optimization algorithms and state regulation. This control design is developed for simple linear time-invariant systems and then extended for a class of feedback linearizable nonlinear systems. The two main optimization algorithms – line search and trust region methods – are analyzed for robustness. Finite-time and asymptotic state regulators are put forward for linear and nonlinear systems respectively. Further design flexibility is achieved u...

  6. Mechanical Modelling of Pultrusion Process: 2D and 3D Numerical Approaches

    DEFF Research Database (Denmark)

    Baran, Ismet; Hattel, Jesper Henri; Akkerman, Remko

    2015-01-01

    The process induced variations such as residual stresses and distortions are a critical issue in pultrusion, since they affect the structural behavior as well as the mechanical properties and geometrical precision of the final product. In order to capture and investigate these variations......, a mechanical analysis should be performed. In the present work, the two dimensional (2D) quasi-static plane strain mechanical model for the pultrusion of a thick square profile developed by the authors is further improved using generalized plane strain elements. In addition to that, a more advanced 3D thermo......-chemical-mechanical analysis is carried out using 3D quadratic elements which is a novel application for the numerical modelling of the pultrusion process. It is found that the 2D mechanical models give relatively reasonable and accurate stress and displacement evolutions in the transverse direction as compared to the 3D...

  7. A numerical approach of thermal problems coupling fluid solid and radiation in complex geometries

    International Nuclear Information System (INIS)

    Peniguel, C.; Rupp, I.

    1995-11-01

    In many industrial problems, heat transfer does play an important part. Quite often, radiation, convection and radiation are present simultaneously. This paper presents the numerical tool handling simultaneously these phenomena. Fluid is tackled by the finite element code N3S, radiation (restricted to a non participating medium) and conduction are handled with SYRTHES respectively by a radiosity method and a finite element method. The main originality of the product is that meshes used to solve each phenomenon are completely independent. This allows users to choose the most appropriate spatial discretization for each part or phenomenon. This flexibility requires of course robust and fast data exchange procedures (temperature, convective flux, radiative flux) between the independent grids. This operation is done automatically by the code SYRTHES. One simple problem illustrating the interest of this development is presented at the end of the paper. (author). 6 refs., 8 figs

  8. Cosmic-ray-modified stellar winds. III. A numerical iterative approach

    International Nuclear Information System (INIS)

    Ko, C.M.; Jokipii, J.R.; Webb, G.M.

    1988-01-01

    A numerical iterative method is used to determine the modification of a stellar wind flow with a termination shock by the galactic cosmic rays. A two-fluid model consisting of cosmic rays and thermal stellar wind gas is used in which the cosmic rays are coupled to the background flow via scattering with magnetohydrodynamic waves or irregularities. A polytropic model is used to describe the thermal stellar wind gas, and the cosmic-rays are modeled as a hot, low-density gas with negligible mass flux. The positive galactic cosmic-ray pressure gradient serves to brake the outflowing stellar wind gas, and the cosmic rays modify the location of the critical point of the wind, the location of the shock, the wind fluid velocity profile, and the thermal gas entropy constants on both sides of the shock. The transfer of energy to the cosmic rays results in an outward radial flux of cosmic-ray energy. 21 references

  9. Pressure and tension waves from bubble collapse near a solid boundary: A numerical approach.

    Science.gov (United States)

    Lechner, Christiane; Koch, Max; Lauterborn, Werner; Mettin, Robert

    2017-12-01

    The acoustic waves being generated during the motion of a bubble in water near a solid boundary are calculated numerically. The open source package OpenFOAM is used for solving the Navier-Stokes equation and extended to include nonlinear acoustic wave effects via the Tait equation for water. A bubble model with a small amount of gas is chosen, the gas obeying an adiabatic law. A bubble starting from a small size with high internal pressure near a flat, solid boundary is studied. The sequence of events from bubble growth via axial microjet formation, jet impact, annular nanojet formation, torus-bubble collapse, and bubble rebound to second collapse is described. The different pressure and tension waves with their propagation properties are demonstrated.

  10. A Numerical Approach to Determine Attitude Dynamics of Floating Bodies with Irregular Configurations

    Directory of Open Access Journals (Sweden)

    Jiann-Lin Chen

    2014-07-01

    Full Text Available This study acquires the attitude dynamics of floating bodies with irregular configurations using an effective computational model, which has been validated theoretically and verified by experiments. By comparison a correlation formula was described to predict inclinations for the floating slender body imitating an excise torpedo. Thereafter a computational model was developed to account for bodies with attitudes in more general situations. For demonstration, a submersible was simulated to reveal that the inclinations vary abruptly around certain longitudinal locations of center of gravity. The property variations during water ingress assumption were presented. Similar to the virtue tank, an innovative concept of building the numerical data base for a specific floating body has been proposed, by which the position of its center of gravity can be obtained by interpolation from attitude data in tables as determined by the present computational model.

  11. Development and characterization of nanoparticulate formulation of a water soluble prodrug of dexamethasone by HIP complexation.

    Science.gov (United States)

    Gaudana, Ripal; Parenky, Ashwin; Vaishya, Ravi; Samanta, Swapan K; Mitra, Ashim K

    2011-01-01

    The objective of this study was to develop and characterize a nanoparticulate-based sustained release formulation of a water soluble dipeptide prodrug of dexamethasone, valine-valine-dexamethasone (VVD). Being hydrophilic in nature, it readily leaches out in the external aqueous medium and hence partitions poorly into the polymeric matrix resulting in minimal entrapment in nanoparticles. Hence, hydrophobic ion pairing (HIP) complexation of the prodrug was employed with dextran sulphate as a complexing polymer. A novel, solid in oil in water emulsion method was employed to encapsulate the prodrug in HIP complex form in poly(lactic-co-glycolic acid) matrix. Nanoparticles were characterized with respect to size, zeta potential, crystallinity of entrapped drug and surface morphology. A significant enhancement in the entrapment of the prodrug in nanoparticles was achieved. Finally, a simple yet novel method was developed which can also be applicable to encapsulate other charged hydrophilic molecules, such as peptides and proteins.

  12. Esterase-sensitive sulfur dioxide prodrugs inspired by modified Julia olefination.

    Science.gov (United States)

    Wang, Wenyi; Wang, Binghe

    2017-09-12

    Sulfur dioxide (SO 2 ) is an endogenously produced gaseous molecule, and is emerging as a potential gasotransmitter. Herein, we describe the first series of esterase-sensitive prodrugs inspired by modified Julia olefination as SO 2 donors.

  13. Synthesis and antimalarial evaluation of prodrugs of novel fosmidomycin analogues.

    Science.gov (United States)

    Faísca Phillips, Ana Maria; Nogueira, Fátima; Murtinheira, Fernanda; Barros, Maria Teresa

    2015-01-01

    The continuous development of drug resistance by Plasmodium falciparum, the agent responsible for the most severe forms of malaria, creates the need for the development of novel drugs to fight this disease. Fosmidomycin is an effective antimalarial and potent antibiotic, known to act by inhibiting the enzyme 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), essential for the synthesis of isoprenoids in eubacteria and plasmodia, but not in humans. In this study, novel constrained cyclic prodrug analogues of fosmidomycin were synthesized. One, in which the hydroxamate function is incorporated into a six-membered ring, was found have higher antimalarial activity than fosmidomycin against the chloroquine and mefloquine resistant P. falciparum Dd2 strain. In addition, it showed very low cytotoxicity against cultured human cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Numerical methodologies for investigation of moderate-velocity flow using a hybrid computational fluid dynamics - molecular dynamics simulation approach

    International Nuclear Information System (INIS)

    Ko, Soon Heum; Kim, Na Yong; Nikitopoulos, Dimitris E.; Moldovan, Dorel; Jha, Shantenu

    2014-01-01

    Numerical approaches are presented to minimize the statistical errors inherently present due to finite sampling and the presence of thermal fluctuations in the molecular region of a hybrid computational fluid dynamics (CFD) - molecular dynamics (MD) flow solution. Near the fluid-solid interface the hybrid CFD-MD simulation approach provides a more accurate solution, especially in the presence of significant molecular-level phenomena, than the traditional continuum-based simulation techniques. It also involves less computational cost than the pure particle-based MD. Despite these advantages the hybrid CFD-MD methodology has been applied mostly in flow studies at high velocities, mainly because of the higher statistical errors associated with low velocities. As an alternative to the costly increase of the size of the MD region to decrease statistical errors, we investigate a few numerical approaches that reduce sampling noise of the solution at moderate-velocities. These methods are based on sampling of multiple simulation replicas and linear regression of multiple spatial/temporal samples. We discuss the advantages and disadvantages of each technique in the perspective of solution accuracy and computational cost.

  15. Preparation, characterization and in vitro evaluation of a new nucleotide analogue prodrug cyclodextrin inclusion complexes.

    OpenAIRE

    Diab , Roudayna; Jordheim , Lars P; Degobert , Ghania; Peyrottes , Suzanne; Périgaud , Christian; Dumontet , Charles; Fessi , Hatem

    2009-01-01

    International audience; Bis(tbutyl-S-acyl-2-thioethyl)-cytidine monophosophate is a new cytotoxic mononucleotide prodrug which have been developed to reverse the cellular resistance to nucleoside analogues. Unfortunately, its in vivo utilisation was hampered by its poor water solubility, raising the need of a molecular vector capable to mask its physicochemical characteristics although without affecting its cytotoxic activity. Hydroxypropyl-beta-cyclodextrin was used to prepare the prodrug in...

  16. Synthesis, characterization and in vitro release performance of the pegylated valnemulin prodrug

    Science.gov (United States)

    DONG, Xinrui; SHU, Xueye; WANG, Yingnan; NIU, Zhaohuan; XU, Shixia; ZHANG, Yue; ZHAO, Shuchun

    2017-01-01

    Valnemulin, successfully developed by Sandoz in 1984, is a new generation derivative of pleuromutilin related to tiamulin. Valnemulin has low water-solubility, a short half-life period, low bioavailability, and instability. The application of valnemulin was restricted. Therefore, finding a more moderate delivery system is necessary to improve the shortcomings of valnemulin. The purpose of the study was to improve the strong stability and the irritation caused by of valnemulin hydrochloride power through pegylated-valnemulin prodrug mode. The prepared pegylated-valnemulin prodrug was characterized and evaluated by in vitro release performance under buffer solutions with pH levels of 7.4 and 3.6. The loading rate of valnemulin in PEG-succinic-valnemulin prodrug was determined by ultraviolet spectrophotometer and high performance liquid chromatography (HPLC). HPLC with evaporative light scattering detector was applied to determine the amount of PEG-succinic acid. The loading rate of valnemulin in PEG-succinic-valnemulin prodrug was 6.46%. PEG-succinic-valnemulin prodrug demonstrated a satisfactory solubility of valnemulin with 523 mg·ml−1 and excellent stability verified by the stability experiment. The result of the in vitro release test showed that the prepared PEG-valnemulin prodrug has controlled release ability and the release rate of valnemulin from PEG-valnemulin prodrug with a pH of 7.4 was 64.98%, which was higher than that of pH3.6 with release rate of 31.90%. Therefore, the prepared PEG-succinic-valnemulin prodrug has great application potential. PMID:29187697

  17. Pt(IV) complexes as prodrugs for cisplatin.

    Science.gov (United States)

    Shi, Yi; Liu, Shu-An; Kerwood, Deborah J; Goodisman, Jerry; Dabrowiak, James C

    2012-02-01

    The antitumor effects of platinum(IV) complexes, considered prodrugs for cisplatin, are believed to be due to biological reduction of Pt(IV) to Pt(II), with the reduction products binding to DNA and other cellular targets. In this work we used pBR322 DNA to capture the products of reduction of oxoplatin, c,t,c-[PtCl(2)(OH)(2)(NH(3))(2)], 3, and a carboxylate-modified analog, c,t,c-[PtCl(2)(OH)(O(2)CCH(2)CH(2)CO(2)H)(NH(3))(2)], 4, by ascorbic acid (AsA) or glutathione (GSH). Since carbonate plays a significant role in the speciation of platinum complexes in solution, we also investigated the effects of carbonate on the reduction/DNA-binding process. In pH 7.4 buffer in the absence of carbonate, both 3 and 4 are reduced by AsA to cisplatin (confirmed using ((195))Pt NMR), which binds to and unwinds closed circular DNA in a manner consistent with the formation of the well-known 1, 2 intrastrand DNA crosslink. However, when GSH is used as the reducing agent for 3 and 4, ((195))Pt NMR shows that cisplatin is not produced in the reaction medium. Although the Pt(II) products bind to closed circular DNA, their effect on the mobility of Form I DNA is different from that produced by cisplatin. When physiological carbonate is present in the reduction medium, ((13))C NMR shows that Pt(II) carbonato complexes form which block or impede platinum binding to DNA. The results of the study vis-à-vis the ability of the Pt(IV) complexes to act as prodrugs for cisplatin are discussed. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Review on chemical processes around the facilities in deep underground and study on numerical approach to evaluate them

    International Nuclear Information System (INIS)

    Sawada, Masataka

    2003-01-01

    The facilities for radioactive waste repositories are constructed in deep underground. Various chemical reactions including microbial activities may affect the long-term performance of the barrier system. An advancement of the evaluation method for the long-term behavior of barrier materials is desired. One of the efficient approaches is numerical simulation based on modeling of chemical processes. In the first part of this report, chemical processes and microbial reactions that can affect the performance of facilities in deep underground are reviewed. For example, dissolution and precipitation of minerals composing bentonite and rock are caused by highly alkaline water from cementitious materials. Numerical approaches to the chemical processes are also studied. Most chemical processes are reactions between groundwater (or solutes in it) and minerals composing barrier materials. So they can be simulated by coupled reaction rate transport analyses. Some analysis codes are developed and applied to problems in radioactive waste disposal. Microbial reaction rate can be modeled using the growth equation of microorganisms. In order to evaluate the performance of the barrier system after altered by chemical processes, not only the change in composition but also properties of altered materials is required to be obtained as output of numerical simulation. If the relationships between reaction rate and material properties are obtained, time history and spatial distribution of material properties can also be obtained by the coupled reaction rate transport analysis. At present, modeling study on the relationships between them is not sufficient, and obtaining such relationships using both theoretical and experimental approaches are also an important research target. (author)

  19. Nitrogen Fate in a Phreatic Fluviokarst Watershed: a Stable Isotope, Sediment Tracing, and Numerical Modeling Approach

    Science.gov (United States)

    Husic, A.; Fox, J.; Ford, W. I., III; Agouridis, C.; Currens, J. C.; Taylor, C. J.

    2017-12-01

    Sediment tracing tools provide an insight into provenance, fate, and transport of sediment and, when coupled to stable isotopes, can elucidate in-stream biogeochemical processes. Particulate nitrogen fate in fluviokarst systems is a relatively unexplored area of research partially due to the complex hydrodynamics at play in karst systems. Karst topography includes turbulent conduits that transport groundwater and contaminants at speeds more typical of open channel flows than laminar Darcian flows. While it is accepted that karst hydro-geomorphology represents a hybrid surface-subsurface system for fluid, further investigation is needed to determine whether, and to what extent, karst systems behave like surface agricultural streams or porous media aquifers with respect to their role in nitrogen cycling. Our objective is to gain an understanding of in-conduit nitrogen processes and their effect on net nitrogen-exports from karst springs to larger waterbodies. The authors apply water, sediment, carbon, and nitrogen tracing techniques to analyze water for nitrate, sediment carbon and nitrogen, and stable sediment nitrogen isotope (δ15N). Thereafter, a new numerical model is formulated that: simulates dissolved inorganic nitrogen and sediment nitrogen transformations in the phreatic karst conduit; couples carbon turnover and nitrogen transformations in the model structure; and simulates the nitrogen stable isotope mass balance for the dissolved and sediment phases. Nitrogen tracing data results show a significant increase in δ15N of sediment nitrogen at the spring outlet relative to karst inputs indicating the potential for isotope fractionation during dissolved N uptake by bed sediments in the conduit and during denitrification within bed sediments. The new numerical modeling structure is then used to reproduce the data results and provide an estimate of the relative dominance of N uptake and denitrification within the surficial sediments of the karst conduit system

  20. Simplified approaches for the numerical simulation of welding processes with filler material

    Energy Technology Data Exchange (ETDEWEB)

    Carmignani, B.; Toselli, G. [ENEA, Divisione Fisica Applicata, Centro Ricerche Ezio Clementel, Bologna (Italy)

    2001-07-01

    Due to the very high computation times, required by the methodologies pointed out during the studies carried out at ENEA-Bologna concerning the numerical simulations of welds with filler material of steel pieces of high thickness (studies presented also at the 12. and 13. International ABAQUS Users' Conferences), new simplified methodologies have been proposed and applied to an experimental model of significant dimensions. (These studies are of interest in the nuclear field for the construction of the toroidal field coil case, TFCC, for the international thermonuclear experimental reactor, ITER machine). In this paper these new methodologies are presented together the obtained results, which have been compared, successfully, with the ones obtained by the use of the previous numerical methodologies considered and also with the corresponding experimental measures. These new calculation techniques are in course of application for the simulation of welds of pieces constituting a real component of ITER TF coil case. [Italian] A causa dei tempi di calcolo molto elevati richiesti dalle metodologie individuate e messe a punto durante gli studi eseguiti in ENEA-Bologna riguardanti le simulazioni numeriche di saldature, con apporto di materiale, di pezzi di acciaio di grande spessore (studi presentati anche alle precedenti Conferenze Utenti ABAQUS, 12{sup 0} e 13{sup 0} ABAQUS Users' Conferences), sono state cercate e proposte nuove metodologie semplificate, che sono state poi applicate ad un modello sperimentale di dimensioni significative. (Si ricorda che questi studi sono di interesse nel campo nucleare per la costruzione delle casse per contenere le bobine che daranno luogo al campo magnetico della macchina ITER, reattore internazione sperimentale termonucleare). Nel lavoro qui presentato sono descritte queste nuove metodologie e sono riportati i risultati ottenuti dalla loro applicazione unitamente ai confronti (abbastanza soddisfacenti) con i risultati

  1. Minimal duality breaking in the Kallen-Lehman approach to 3D Ising model: A numerical test

    International Nuclear Information System (INIS)

    Astorino, Marco; Canfora, Fabrizio; Martinez, Cristian; Parisi, Luca

    2008-01-01

    A Kallen-Lehman approach to 3D Ising model is analyzed numerically both at low and high temperatures. It is shown that, even assuming a minimal duality breaking, one can fix three parameters of the model to get a very good agreement with the Monte Carlo results at high temperatures. With the same parameters the agreement is satisfactory both at low and near critical temperatures. How to improve the agreement with Monte Carlo results by introducing a more general duality breaking is shortly discussed

  2. An Integrated Approach for the Numerical Modelling of the Spray Forming Process

    DEFF Research Database (Denmark)

    Hattel, Jesper; Thorborg, Jesper; Pryds, Nini

    2003-01-01

    In this paper, an integrated approach for modelling the entire spray forming process is presented. The basis for the analysis is a recently developed model which extents previous studies and includes the interaction between an array of droplets and the enveloping gas. The formulation of the depos......In this paper, an integrated approach for modelling the entire spray forming process is presented. The basis for the analysis is a recently developed model which extents previous studies and includes the interaction between an array of droplets and the enveloping gas. The formulation...... is in fact the summation of "local" droplet size distributions along the r-axis. Furthermore, the deposition model proposed in the paper involves both the sticking efficiency of the droplets to the substrate as well as a geometrical model involving the effects of shadowing for the production of billet...

  3. Nonlinear mechanics of thin-walled structures asymptotics, direct approach and numerical analysis

    CERN Document Server

    Vetyukov, Yury

    2014-01-01

    This book presents a hybrid approach to the mechanics of thin bodies. Classical theories of rods, plates and shells with constrained shear are based on asymptotic splitting of the equations and boundary conditions of three-dimensional elasticity. The asymptotic solutions become accurate as the thickness decreases, and the three-dimensional fields of stresses and displacements can be determined. The analysis includes practically important effects of electromechanical coupling and material inhomogeneity. The extension to the geometrically nonlinear range uses the direct approach based on the principle of virtual work. Vibrations and buckling of pre-stressed structures are studied with the help of linearized incremental formulations, and direct tensor calculus rounds out the list of analytical techniques used throughout the book. A novel theory of thin-walled rods of open profile is subsequently developed from the models of rods and shells, and traditionally applied equations are proven to be asymptotically exa...

  4. Numerical Investigation of Desulfurization Kinetics in Gas-Stirred Ladles by a Quick Modeling Analysis Approach

    Science.gov (United States)

    Cao, Qing; Nastac, Laurentiu; Pitts-Baggett, April; Yu, Qiulin

    2018-03-01

    A quick modeling analysis approach for predicting the slag-steel reaction and desulfurization kinetics in argon gas-stirred ladles has been developed in this study. The model consists of two uncoupled components: (i) a computational fluid dynamics (CFD) model for predicting the fluid flow and the characteristics of slag-steel interface, and (ii) a multicomponent reaction kinetics model for calculating the desulfurization evolution. The steel-slag interfacial area and mass transfer coefficients predicted by the CFD simulation are used as the processing data for the reaction model. Since the desulfurization predictions are uncoupled from the CFD simulation, the computational time of this uncoupled predictive approach is decreased by at least 100 times for each case study when compared with the CFD-reaction kinetics fully coupled model. The uncoupled modeling approach was validated by comparing the evolution of steel and slag compositions with the experimentally measured data during ladle metallurgical furnace (LMF) processing at Nucor Steel Tuscaloosa, Inc. Then, the validated approach was applied to investigate the effects of the initial steel and slag compositions, as well as different types of additions during the refining process on the desulfurization efficiency. The results revealed that the sulfur distribution ratio and the desulfurization reaction can be promoted by making Al and CaO additions during the refining process. It was also shown that by increasing the initial Al content in liquid steel, both Al oxidation and desulfurization rates rapidly increase. In addition, it was found that the variation of the initial Si content in steel has no significant influence on the desulfurization rate. Lastly, if the initial CaO content in slag is increased or the initial Al2O3 content is decreased in the fluid-slag compositional range, the desulfurization rate can be improved significantly during the LMF process.

  5. Numerical Investigation of Desulfurization Kinetics in Gas-Stirred Ladles by a Quick Modeling Analysis Approach

    Science.gov (United States)

    Cao, Qing; Nastac, Laurentiu; Pitts-Baggett, April; Yu, Qiulin

    2018-06-01

    A quick modeling analysis approach for predicting the slag-steel reaction and desulfurization kinetics in argon gas-stirred ladles has been developed in this study. The model consists of two uncoupled components: (i) a computational fluid dynamics (CFD) model for predicting the fluid flow and the characteristics of slag-steel interface, and (ii) a multicomponent reaction kinetics model for calculating the desulfurization evolution. The steel-slag interfacial area and mass transfer coefficients predicted by the CFD simulation are used as the processing data for the reaction model. Since the desulfurization predictions are uncoupled from the CFD simulation, the computational time of this uncoupled predictive approach is decreased by at least 100 times for each case study when compared with the CFD-reaction kinetics fully coupled model. The uncoupled modeling approach was validated by comparing the evolution of steel and slag compositions with the experimentally measured data during ladle metallurgical furnace (LMF) processing at Nucor Steel Tuscaloosa, Inc. Then, the validated approach was applied to investigate the effects of the initial steel and slag compositions, as well as different types of additions during the refining process on the desulfurization efficiency. The results revealed that the sulfur distribution ratio and the desulfurization reaction can be promoted by making Al and CaO additions during the refining process. It was also shown that by increasing the initial Al content in liquid steel, both Al oxidation and desulfurization rates rapidly increase. In addition, it was found that the variation of the initial Si content in steel has no significant influence on the desulfurization rate. Lastly, if the initial CaO content in slag is increased or the initial Al2O3 content is decreased in the fluid-slag compositional range, the desulfurization rate can be improved significantly during the LMF process.

  6. Gamma ray self-attenuation correction: a simple numerical approach and its validation

    International Nuclear Information System (INIS)

    Agarwal, Chhavi; Poi, Sanhita; Mhatre, Amol; Goswami, A.

    2009-03-01

    A hybrid Monte Carlo method for gamma ray attenuation correction has been developed. The method has been applied to some common counting geometries like cylinder, box, sphere and disc. The method has been validated theoretically and experimentally over a wide range of transmittance and sample-to-detector distances. The advantage of the approach is that it is common to all sample geometries and can be used at all sample-to detector distances. (author)

  7. Numerical modeling of hydrodynamics and sediment transport—an integrated approach

    Science.gov (United States)

    Gic-Grusza, Gabriela; Dudkowska, Aleksandra

    2017-10-01

    Point measurement-based estimation of bedload transport in the coastal zone is very difficult. The only way to assess the magnitude and direction of bedload transport in larger areas, particularly those characterized by complex bottom topography and hydrodynamics, is to use a holistic approach. This requires modeling of waves, currents, and the critical bed shear stress and bedload transport magnitude, with a due consideration to the realistic bathymetry and distribution of surface sediment types. Such a holistic approach is presented in this paper which describes modeling of bedload transport in the Gulf of Gdańsk. Extreme storm conditions defined based on 138-year NOAA data were assumed. The SWAN model (Booij et al. 1999) was used to define wind-wave fields, whereas wave-induced currents were calculated using the Kołodko and Gic-Grusza (2015) model, and the magnitude of bedload transport was estimated using the modified Meyer-Peter and Müller (1948) formula. The calculations were performed using a GIS model. The results obtained are innovative. The approach presented appears to be a valuable source of information on bedload transport in the coastal zone.

  8. Axial-Symmetry Numerical Approaches for Noise Predicting and Attenuating of Rifle Shooting with Suppressors

    Directory of Open Access Journals (Sweden)

    Shi-Wei Lo

    2011-01-01

    Full Text Available The moving bullet out of a rifle barrel is propelled by a fired explosive charge. Subsequently, a disturbed muzzle blast wave is initiated which lasts several milliseconds. In this study, axially symmetric, unsteady, Large Eddy Simulation (LES, and Ffowcs Williams and Hawkins (FWH equations were solved by the implicit-time formulation. For the spatial discretization, second order upwind scheme was employed. In addition, dynamic mesh model was used to where the ballistic domain changed with time due to the motion of bullet. Results obtained for muzzle flow field and for noise recorded were compared with those obtained from experimental data; these two batches of results were in agreement. Five cases of gunshot including one model of an unsuppressed rifle and four models of suppressors were simulated. Besides, serial images of species distributions and velocity vectors-pressure contours in suppressors and near muzzle field were displayed. The sound pressure levels (dB in far field that were post-processed by the fast Fourier transform (FFT were compared. The proposed physical model and the numerical simulations used in the present work are expected to be extended to solve other shooting weapon problems with three-dimensional and complex geometries.

  9. Maximum power tracking in WECS (Wind energy conversion systems) via numerical and stochastic approaches

    International Nuclear Information System (INIS)

    Elnaggar, M.; Abdel Fattah, H.A.; Elshafei, A.L.

    2014-01-01

    This paper presents a complete design of a two-level control system to capture maximum power in wind energy conversion systems. The upper level of the proposed control system adopts a modified line search optimization algorithm to determine a setpoint for the wind turbine speed. The calculated speed setpoint corresponds to the maximum power point at given operating conditions. The speed setpoint is fed to a generalized predictive controller at the lower level of the control system. A different formulation, that treats the aerodynamic torque as a disturbance, is postulated to derive the control law. The objective is to accurately track the setpoint while keeping the control action free from unacceptably fast or frequent variations. Simulation results based on a realistic model of a 1.5 MW wind turbine confirm the superiority of the proposed control scheme to the conventional ones. - Highlights: • The structure of a MPPT (maximum power point tracking) scheme is presented. • The scheme is divided into the optimization algorithm and the tracking controller. • The optimization algorithm is based on an online line search numerical algorithm. • The tracking controller is treating the aerodynamics torque as a loop disturbance. • The control technique is simulated with stochastic wind speed by Simulink and FAST

  10. The Estuaries Contribution for Supplying Nutrients (N and P) in Jepara Using Numerical Modelling Approach

    Science.gov (United States)

    Maslukah, Lilik; Yulina Wulandari, Sri; Budi Prasetyawan, Indra

    2018-02-01

    Coastal water is dynamic area since it is influenced by both ocean and land. It has high primary productivity that determined fishing ground area. Increased supply of nutrients in coastal water is significantly influenced by seasons and the presence of the river estuaries carrying water masses from the mainland. This study focused on the rivers (Serang, Wiso, Grenjengan Mlonggo and Pasokan rivers) contributed nutrients supply spatially and temporally to Jepara water using numerical modeling. The results showed nutrients content of N (Nitrate) and P (Phosphate) from those rivers were 39.19 tons N/month and 2.26 tons P/month in June, 19.94 tons N/month and 1.96 tons P/month in August. From simulation modeling nutrient of N and P showed that the distribution pattern of N and P was larger during the neap tide than the spring tide. Furthermore, compared with the other rivers, Serang river was the highest nutrient supplier to Jepara water.

  11. Towards more sustainable management of European food waste: Methodological approach and numerical application.

    Science.gov (United States)

    Manfredi, Simone; Cristobal, Jorge

    2016-09-01

    Trying to respond to the latest policy needs, the work presented in this article aims at developing a life-cycle based framework methodology to quantitatively evaluate the environmental and economic sustainability of European food waste management options. The methodology is structured into six steps aimed at defining boundaries and scope of the evaluation, evaluating environmental and economic impacts and identifying best performing options. The methodology is able to accommodate additional assessment criteria, for example the social dimension of sustainability, thus moving towards a comprehensive sustainability assessment framework. A numerical case study is also developed to provide an example of application of the proposed methodology to an average European context. Different options for food waste treatment are compared, including landfilling, composting, anaerobic digestion and incineration. The environmental dimension is evaluated with the software EASETECH, while the economic assessment is conducted based on different indicators expressing the costs associated with food waste management. Results show that the proposed methodology allows for a straightforward identification of the most sustainable options for food waste, thus can provide factual support to decision/policy making. However, it was also observed that results markedly depend on a number of user-defined assumptions, for example on the choice of the indicators to express the environmental and economic performance. © The Author(s) 2016.

  12. Analysis of selected problems of biomass combustion process in batch boilers - experimental and numerical approach

    Science.gov (United States)

    Szubel, Mateusz

    2016-03-01

    It is possible to list numerous groups of heating units that are used in households, such as boilers, stoves and units used as supporting heat sources, namely fireplaces. In each case, however, the same operational problems may be evoked [1]. To understand the causes of energy losses in a boiler system, a proper definition of significant elements of the unit's heat balance is necessary. In the group of energy losses, the flue gas loss and the incomplete combustion loss are the most significant factors. The problem with the loss resulting from incomplete combustion, which is related to the presence of combustible substances in the exhaust, is especially significant in case of biomass boilers [2, 3]. The paper presents results of the research and the optimisation of the biomass combustion process in the 180 kW batch boiler. The studies described have been focused on the reduction of the pollutants emission, which was primarily realised by the modifications of the air feeding system. Results of the experiments and the CFD simulations have been compared and discussed. Both in case of the model as well as the experiment, positive influence of the modifications on the emission have been observed.

  13. Analysis of selected problems of biomass combustion process in batch boilers - experimental and numerical approach

    Directory of Open Access Journals (Sweden)

    Szubel Mateusz

    2016-01-01

    Full Text Available It is possible to list numerous groups of heating units that are used in households, such as boilers, stoves and units used as supporting heat sources, namely fireplaces. In each case, however, the same operational problems may be evoked [1]. To understand the causes of energy losses in a boiler system, a proper definition of significant elements of the unit’s heat balance is necessary. In the group of energy losses, the flue gas loss and the incomplete combustion loss are the most significant factors. The problem with the loss resulting from incomplete combustion, which is related to the presence of combustible substances in the exhaust, is especially significant in case of biomass boilers [2, 3]. The paper presents results of the research and the optimisation of the biomass combustion process in the 180 kW batch boiler. The studies described have been focused on the reduction of the pollutants emission, which was primarily realised by the modifications of the air feeding system. Results of the experiments and the CFD simulations have been compared and discussed. Both in case of the model as well as the experiment, positive influence of the modifications on the emission have been observed.

  14. Cellular Spacing Selection During the Directional Solidification of Binary Alloys. A Numerical Approach

    Science.gov (United States)

    Catalina, Adrian V.; Sen, S.; Rose, M. Franklin (Technical Monitor)

    2001-01-01

    The evolution of cellular solid/liquid interfaces from an initially unstable planar front was studied by means of a two-dimensional computer simulation. The developed numerical model makes use of an interface tracking procedure and has the capability to describe the dynamics of the interface morphology based on local changes of the thermodynamic conditions. The fundamental physics of this formulation was validated against experimental microgravity results and the predictions of the analytical linear stability theory. The performed simulations revealed that in certain conditions, based on a competitive growth mechanism, an interface could become unstable to random perturbations of infinitesimal amplitude even at wavelengths smaller than the neutral wavelength, lambda(sub c), predicted by the linear stability theory. Furthermore, two main stages of spacing selection have been identified. In the first stage, at low perturbations amplitude, the selection mechanism is driven by the maximum growth rate of instabilities while in the second stage the selection is influenced by nonlinear phenomena caused by the interactions between the neighboring cells. Comparison of these predictions with other existing theories of pattern formation and experimental results will be discussed.

  15. Radiative heat transfer in honeycomb structures-New simple analytical and numerical approaches

    International Nuclear Information System (INIS)

    Baillis, D; Coquard, R; Randrianalisoa, J

    2012-01-01

    Porous Honeycomb Structures present the interest of combining, at the same time, high thermal insulating properties, low density and sufficient mechanical resistance. However, their thermal properties remain relatively unexplored. The aim of this study is the modelling of the combined heat transfer and especially radiative heat transfer through this type of anisotropic porous material. The equivalent radiative properties of the material are determined using ray-tracing procedures inside the honeycomb porous structure. From computational ray-tracing results, simple new analytical relations have been deduced. These useful analytical relations permit to determine radiative properties such as extinction, absorption and scattering coefficients and phase function functions of cell dimensions and optical properties of cell walls. The radiative properties of honeycomb material strongly depend on the direction of propagation. From the radiative properties computed, we have estimated the radiative heat flux passing through slabs of honeycomb core materials submitted to a 1-D temperature difference between a hot and a cold plate. We have compared numerical results obtained from Discrete Ordinate Method with analytical results obtained from Rosseland-Deissler approximation. This approximation is usually used in the case of isotropic materials. We have extended it to anisotropic honeycomb materials. Indeed a mean over incident directions of Rosseland extinction coefficient is proposed. Results tend to show that Rosseland-Deissler extended approximation can be used as a first approximation. Deviation on radiative conductivity obtained from Rosseland-Deissler approximation and from the Discrete Ordinated Method are lower than 6.7% for all the cases studied.

  16. Revisiting Formability and Failure of AISI304 Sheets in SPIF: Experimental Approach and Numerical Validation

    Directory of Open Access Journals (Sweden)

    Gabriel Centeno

    2017-11-01

    Full Text Available Single Point Incremental Forming (SPIF is a flexible and economic manufacturing process with a strong potential for manufacturing small and medium batches of highly customized parts. Formability and failure in SPIF have been intensively discussed in recent years, especially because this process allows stable plastic deformation well above the conventional forming limits, as this enhanced formability is only achievable within a certain range of process parameters depending on the material type. This paper analyzes formability and failure of AISI304-H111 sheets deformed by SPIF compared to conventional testing conditions (including Nakazima and stretch-bending tests. With this purpose, experimental tests in SPIF and stretch-bending were carried out and a numerical model of SPIF is performed. The results allow the authors to establish the following contributions regarding SPIF: (i the setting of the limits of the formability enhancement when small tool diameters are used, (ii the evolution of the crack when failure is attained and (iii the determination of the conditions upon which necking is suppressed, leading directly to ductile fracture in SPIF.

  17. An integrated DEA PCA numerical taxonomy approach for energy efficiency assessment and consumption optimization in energy intensive manufacturing sectors

    International Nuclear Information System (INIS)

    Azadeh, A.; Amalnick, M.S.; Ghaderi, S.F.; Asadzadeh, S.M.

    2007-01-01

    This paper introduces an integrated approach based on data envelopment analysis (DEA), principal component analysis (PCA) and numerical taxonomy (NT) for total energy efficiency assessment and optimization in energy intensive manufacturing sectors. Total energy efficiency assessment and optimization of the proposed approach considers structural indicators in addition conventional consumption and manufacturing sector output indicators. The validity of the DEA model is verified and validated by PCA and NT through Spearman correlation experiment. Moreover, the proposed approach uses the measure-specific super-efficiency DEA model for sensitivity analysis to determine the critical energy carriers. Four energy intensive manufacturing sectors are discussed in this paper: iron and steel, pulp and paper, petroleum refining and cement manufacturing sectors. To show superiority and applicability, the proposed approach has been applied to refinery sub-sectors of some OECD (Organization for Economic Cooperation and Development) countries. This study has several unique features which are: (1) a total approach which considers structural indicators in addition to conventional energy efficiency indicators; (2) a verification and validation mechanism for DEA by PCA and NT and (3) utilization of DEA for total energy efficiency assessment and consumption optimization of energy intensive manufacturing sectors

  18. Numeric, Agent-based or System dynamics model? Which modeling approach is the best for vast population simulation?

    Science.gov (United States)

    Cimler, Richard; Tomaskova, Hana; Kuhnova, Jitka; Dolezal, Ondrej; Pscheidl, Pavel; Kuca, Kamil

    2018-02-01

    Alzheimer's disease is one of the most common mental illnesses. It is posited that more than 25 % of the population is affected by some mental disease during their lifetime. Treatment of each patient draws resources from the economy concerned. Therefore, it is important to quantify the potential economic impact. Agent-based, system dynamics and numerical approaches to dynamic modeling of the population of the European Union and its patients with Alzheimer's disease are presented in this article. Simulations, their characteristics, and the results from different modeling tools are compared. The results of these approaches are compared with EU population growth predictions from the statistical office of the EU by Eurostat. The methodology of a creation of the models is described and all three modeling approaches are compared. The suitability of each modeling approach for the population modeling is discussed. In this case study, all three approaches gave us the results corresponding with the EU population prediction. Moreover, we were able to predict the number of patients with AD and, based on the modeling method, we were also able to monitor different characteristics of the population. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Simulation of a Diode Pumped Alkali Laser; a Three Level Numerical Approach

    Science.gov (United States)

    2010-03-01

    APPROACH THESIS Presented to the Faculty Department of Engineering Physics Graduate School of Engineering and Management Air Force Institute of...1 26.24 * 10-9 H*Lewis Hz*L; A32@85D = 0; A32@87D = 0; III. Parameters Printed by Mathematica for Students 65 III. Parameters A. Enviromental ...Institute of Technology Graduate School of Engineering and Management (AFIT/EN) 2950 Hobson Way WPAFB OH 45433-7765 AFIT/GAP/ENP/10-M06 HEL-JTO 901

  20. Principles and Approaches for Numerical Modelling of Sediment Transport in Sewers

    DEFF Research Database (Denmark)

    Mark, Ole; Appelgren, Cecilia; Larsen, Torben

    1995-01-01

    A study has been carried out with the objectives of describing the effect of sediment deposits on the hydraulic capacity of sewer systems and to investigate the sediment transport in sewer systems. A result of the study is a mathematical model MOUSE ST which describes sediment transport in sewers....... This paper discusses the applicability and the limitations of various modelling approaches and sediment transport formulations in in MOUSE ST. Further, the paper presents a simple application of MOUSE ST to the Rya catchment in Gothenburg, Sweden....

  1. Principles and approaches for numerical modelling of sediment transport in sewers

    DEFF Research Database (Denmark)

    Mark, Ole; Larsen, Torben; Appelgren, Cecilia

    1994-01-01

    model MOUSE ST which describes the sediment transport in sewers. This paper discusses the applicability and the limitations of various modelling approaches and sediment transport formulations in MOUSE ST. The study was founded by the Swedish Water and Waste Works Association and the Nordic Industrial......A study has been carried out at the University of Aalborg, Denmark and VBB VIAK, Sweden with the objectives to describe the effect of sediment deposits on the hydraulic capacity of sewer systems and to investigate the sediment transport in sewer systems. A results of the study is a mathematical...

  2. HIGH-ENERGY COSMIC-RAY DIFFUSION IN MOLECULAR CLOUDS: A NUMERICAL APPROACH

    International Nuclear Information System (INIS)

    Fatuzzo, M.; Melia, F.; Todd, E.; Adams, F. C.

    2010-01-01

    The propagation of high-energy cosmic rays (CRs) through giant molecular clouds constitutes a fundamental process in astronomy and astrophysics. The diffusion of CRs through these magnetically turbulent environments is often studied through the use of energy-dependent diffusion coefficients, although these are not always well motivated theoretically. Now, however, it is feasible to perform detailed numerical simulations of the diffusion process computationally. While the general problem depends upon both the field structure and particle energy, the analysis may be greatly simplified by dimensionless analysis. That is, for a specified purely turbulent field, the analysis depends almost exclusively on a single parameter-the ratio of the maximum wavelength of the turbulent field cells to the particle gyration radius. For turbulent magnetic fluctuations superimposed over an underlying uniform magnetic field, particle diffusion depends on a second dimensionless parameter that characterizes the ratio of the turbulent to uniform magnetic field energy densities. We consider both of these possibilities and parametrize our results to provide simple quantitative expressions that suitably characterize the diffusion process within molecular cloud environments. Doing so, we find that the simple scaling laws often invoked by the high-energy astrophysics community to model CR diffusion through such regions appear to be fairly robust for the case of a uniform magnetic field with a strong turbulent component, but are only valid up to ∼50 TeV particle energies for a purely turbulent field. These results have important consequences for the analysis of CR processes based on TeV emission spectra associated with dense molecular clouds.

  3. Numerical study comparing RANS and LES approaches on a circulation control airfoil

    International Nuclear Information System (INIS)

    Rumsey, Christopher L.; Nishino, Takafumi

    2011-01-01

    Highlights: → RANS compared with LES for circulation control airfoil. → RANS turbulence models need to account for streamline curvature. → RANS models yield higher lift than LES in spite of predicting similar jet separation. - Abstract: A numerical study over a nominally two-dimensional circulation control airfoil is performed using a large-eddy simulation code and two Reynolds-averaged Navier-Stokes codes. Different Coanda jet blowing conditions are investigated. In addition to investigating the influence of grid density, a comparison is made between incompressible and compressible flow solvers. The incompressible equations are found to yield negligible differences from the compressible equations up to at least a jet exit Mach number of 0.64. The effects of different turbulence models are also studied. Models that do not account for streamline curvature effects tend to predict jet separation from the Coanda surface too late, and can produce non-physical solutions at high blowing rates. Three different turbulence models that account for streamline curvature are compared with each other and with large eddy simulation solutions. All three models are found to predict the Coanda jet separation location reasonably well, but one of the models predicts specific flow field details near the Coanda surface prior to separation much better than the other two. All Reynolds-averaged Navier-Stokes computations produce higher circulation than large eddy simulation computations, with different stagnation point location and greater flow acceleration around the nose onto the upper surface. The precise reasons for the higher circulation are not clear, although it is not solely a function of predicting the jet separation location correctly.

  4. Numerical study comparing RANS and LES approaches on a circulation control airfoil

    Energy Technology Data Exchange (ETDEWEB)

    Rumsey, Christopher L., E-mail: c.l.rumsey@nasa.gov [Computational AeroSciences Branch, NASA Langley Research Center, Hampton, VA 23681-2199 (United States); Nishino, Takafumi [Advanced Supercomputing Division, NASA Ames Research Center, Moffett Field, CA 94035-1000 (United States)

    2011-10-15

    Highlights: > RANS compared with LES for circulation control airfoil. > RANS turbulence models need to account for streamline curvature. > RANS models yield higher lift than LES in spite of predicting similar jet separation. - Abstract: A numerical study over a nominally two-dimensional circulation control airfoil is performed using a large-eddy simulation code and two Reynolds-averaged Navier-Stokes codes. Different Coanda jet blowing conditions are investigated. In addition to investigating the influence of grid density, a comparison is made between incompressible and compressible flow solvers. The incompressible equations are found to yield negligible differences from the compressible equations up to at least a jet exit Mach number of 0.64. The effects of different turbulence models are also studied. Models that do not account for streamline curvature effects tend to predict jet separation from the Coanda surface too late, and can produce non-physical solutions at high blowing rates. Three different turbulence models that account for streamline curvature are compared with each other and with large eddy simulation solutions. All three models are found to predict the Coanda jet separation location reasonably well, but one of the models predicts specific flow field details near the Coanda surface prior to separation much better than the other two. All Reynolds-averaged Navier-Stokes computations produce higher circulation than large eddy simulation computations, with different stagnation point location and greater flow acceleration around the nose onto the upper surface. The precise reasons for the higher circulation are not clear, although it is not solely a function of predicting the jet separation location correctly.

  5. Synthesis and biological evaluation of S-acyl-3-thiopropyl prodrugs of N-phosphonoacetyl-L-aspartate (PALA).

    Science.gov (United States)

    Gagnard, Valérie; Leydet, Alain; Le Mellay, Véronique; Aubenque, Marielle; Morère, Alain; Montero, Jean-Louis

    2003-10-01

    The synthesis of new prodrugs of PALA characterised by the presence of S-acyl-3-thiopropyl, as enzyme-labile groups on the phosphonate moiety of PALA, is reported. The cytotoxic activities of PALA prodrugs were determined against human cell line (SW1573 lung carcinoma cells). A number of prodrugs bearing S-pivaloyl as acyl groups displayed cytotoxic activity in the same order of magnitude of PALA.

  6. Drug Delivery by an Enzyme-Mediated Cyclization of a Lipid Prodrug with Unique Bilayer-Formation Properties

    DEFF Research Database (Denmark)

    Linderoth, Lars; Peters, Günther H.j.; Madsen, Robert

    2009-01-01

    Special delivery: Liposomal drug-delivery systems in which prodrugs are activated specifically by disease-associated enzymes have great potential for the treatment of severe diseases, such as cancer. A new type of phospholipid-based prodrug has the ability to form stable small unilamellar vesicle...... (see picture). Activation of the prodrug vesicles by the enzyme sPLA2 initiates a cyclization reaction, which leads to the release of the drug....

  7. A review of the theoretical and numerical approaches to modeling skyglow: Iterative approach to RTE, MSOS, and two-stream approximation

    International Nuclear Information System (INIS)

    Kocifaj, Miroslav

    2016-01-01

    The study of diffuse light of a night sky is undergoing a renaissance due to the development of inexpensive high performance computers which can significantly reduce the time needed for accurate numerical simulations. Apart from targeted field campaigns, numerical modeling appears to be one of the most attractive and powerful approaches for predicting the diffuse light of a night sky. However, computer-aided simulation of night-sky radiances over any territory and under arbitrary conditions is a complex problem that is difficult to solve. This study addresses three concepts for modeling the artificial light propagation through a turbid stratified atmosphere. Specifically, these are two-stream approximation, iterative approach to Radiative Transfer Equation (RTE) and Method of Successive Orders of Scattering (MSOS). The principles of the methods, their strengths and weaknesses are reviewed with respect to their implications for night-light modeling in different environments. - Highlights: • Three methods for modeling nightsky radiance are reviewed. • The two-stream approximation allows for rapid calculation of radiative fluxes. • The above approach is convenient for modeling large uniformly emitting areas. • SOS is applicable to heterogeneous deployment of well-separated cities or towns. • MSOS is generally CPU less-intensive than traditional 3D RTE.

  8. The numerical multiconfiguration self-consistent field approach for atoms; Der numerische Multiconfiguration Self-Consistent Field-Ansatz fuer Atome

    Energy Technology Data Exchange (ETDEWEB)

    Stiehler, Johannes

    1995-12-15

    The dissertation uses the Multiconfiguration Self-Consistent Field Approach to specify the electronic wave function of N electron atoms in a static electrical field. It presents numerical approaches to describe the wave functions and introduces new methods to compute the numerical Fock equations. Based on results computed with an implemented computer program the universal application, flexibility and high numerical precision of the presented approach is shown. RHF results and for the first time MCSCF results for polarizabilities and hyperpolarizabilities of various states of the atoms He to Kr are discussed. In addition, an application to interpret a plasma spectrum of gallium is presented. (orig.)

  9. Predictability of extreme weather events for NE U.S.: improvement of the numerical prediction using a Bayesian regression approach

    Science.gov (United States)

    Yang, J.; Astitha, M.; Anagnostou, E. N.; Hartman, B.; Kallos, G. B.

    2015-12-01

    Weather prediction accuracy has become very important for the Northeast U.S. given the devastating effects of extreme weather events in the recent years. Weather forecasting systems are used towards building strategies to prevent catastrophic losses for human lives and the environment. Concurrently, weather forecast tools and techniques have evolved with improved forecast skill as numerical prediction techniques are strengthened by increased super-computing resources. In this study, we examine the combination of two state-of-the-science atmospheric models (WRF and RAMS/ICLAMS) by utilizing a Bayesian regression approach to improve the prediction of extreme weather events for NE U.S. The basic concept behind the Bayesian regression approach is to take advantage of the strengths of two atmospheric modeling systems and, similar to the multi-model ensemble approach, limit their weaknesses which are related to systematic and random errors in the numerical prediction of physical processes. The first part of this study is focused on retrospective simulations of seventeen storms that affected the region in the period 2004-2013. Optimal variances are estimated by minimizing the root mean square error and are applied to out-of-sample weather events. The applicability and usefulness of this approach are demonstrated by conducting an error analysis based on in-situ observations from meteorological stations of the National Weather Service (NWS) for wind speed and wind direction, and NCEP Stage IV radar data, mosaicked from the regional multi-sensor for precipitation. The preliminary results indicate a significant improvement in the statistical metrics of the modeled-observed pairs for meteorological variables using various combinations of the sixteen events as predictors of the seventeenth. This presentation will illustrate the implemented methodology and the obtained results for wind speed, wind direction and precipitation, as well as set the research steps that will be

  10. Numerical and analytical approaches to an advection-diffusion problem at small Reynolds number and large Péclet number

    Science.gov (United States)

    Fuller, Nathaniel J.; Licata, Nicholas A.

    2018-05-01

    Obtaining a detailed understanding of the physical interactions between a cell and its environment often requires information about the flow of fluid surrounding the cell. Cells must be able to effectively absorb and discard material in order to survive. Strategies for nutrient acquisition and toxin disposal, which have been evolutionarily selected for their efficacy, should reflect knowledge of the physics underlying this mass transport problem. Motivated by these considerations, in this paper we discuss the results from an undergraduate research project on the advection-diffusion equation at small Reynolds number and large Péclet number. In particular, we consider the problem of mass transport for a Stokesian spherical swimmer. We approach the problem numerically and analytically through a rescaling of the concentration boundary layer. A biophysically motivated first-passage problem for the absorption of material by the swimming cell demonstrates quantitative agreement between the numerical and analytical approaches. We conclude by discussing the connections between our results and the design of smart toxin disposal systems.

  11. Numerical analysis

    CERN Document Server

    Scott, L Ridgway

    2011-01-01

    Computational science is fundamentally changing how technological questions are addressed. The design of aircraft, automobiles, and even racing sailboats is now done by computational simulation. The mathematical foundation of this new approach is numerical analysis, which studies algorithms for computing expressions defined with real numbers. Emphasizing the theory behind the computation, this book provides a rigorous and self-contained introduction to numerical analysis and presents the advanced mathematics that underpin industrial software, including complete details that are missing from most textbooks. Using an inquiry-based learning approach, Numerical Analysis is written in a narrative style, provides historical background, and includes many of the proofs and technical details in exercises. Students will be able to go beyond an elementary understanding of numerical simulation and develop deep insights into the foundations of the subject. They will no longer have to accept the mathematical gaps that ex...

  12. Numerical Approach to Spatial Deterministic-Stochastic Models Arising in Cell Biology.

    Science.gov (United States)

    Schaff, James C; Gao, Fei; Li, Ye; Novak, Igor L; Slepchenko, Boris M

    2016-12-01

    Hybrid deterministic-stochastic methods provide an efficient alternative to a fully stochastic treatment of models which include components with disparate levels of stochasticity. However, general-purpose hybrid solvers for spatially resolved simulations of reaction-diffusion systems are not widely available. Here we describe fundamentals of a general-purpose spatial hybrid method. The method generates realizations of a spatially inhomogeneous hybrid system by appropriately integrating capabilities of a deterministic partial differential equation solver with a popular particle-based stochastic simulator, Smoldyn. Rigorous validation of the algorithm is detailed, using a simple model of calcium 'sparks' as a testbed. The solver is then applied to a deterministic-stochastic model of spontaneous emergence of cell polarity. The approach is general enough to be implemented within biologist-friendly software frameworks such as Virtual Cell.

  13. Numerical Prediction of Combustion-induced Noise using a hybrid LES/CAA approach

    Science.gov (United States)

    Ihme, Matthias; Pitsch, Heinz; Kaltenbacher, Manfred

    2006-11-01

    Noise generation in technical devices is an increasingly important problem. Jet engines in particular produce sound levels that not only are a nuisance but may also impair hearing. The noise emitted by such engines is generated by different sources such as jet exhaust, fans or turbines, and combustion. Whereas the former acoustic mechanisms are reasonably well understood, combustion-generated noise is not. A methodology for the prediction of combustion-generated noise is developed. In this hybrid approach unsteady acoustic source terms are obtained from an LES and the propagation of pressure perturbations are obtained using acoustic analogies. Lighthill's acoustic analogy and a non-linear wave equation, accounting for variable speed of sound, have been employed. Both models are applied to an open diffusion flame. The effects on the far field pressure and directivity due to the variation of speed of sound are analyzed. Results for the sound pressure level will be compared with experimental data.

  14. Numerical optimization approach for resonant electromagnetic vibration transducer designed for random vibration

    International Nuclear Information System (INIS)

    Spreemann, Dirk; Hoffmann, Daniel; Folkmer, Bernd; Manoli, Yiannos

    2008-01-01

    This paper presents a design and optimization strategy for resonant electromagnetic vibration energy harvesting devices. An analytic expression for the magnetic field of cylindrical permanent magnets is used to build up an electromagnetic subsystem model. This subsystem is used to find the optimal resting position of the oscillating mass and to optimize the geometrical parameters (shape and size) of the magnet and coil. The objective function to be investigated is thereby the maximum voltage output of the transducer. An additional mechanical subsystem model based on well-known equations describing the dynamics of spring–mass–damper systems is established to simulate both nonlinear spring characteristics and the effect of internal limit stops. The mechanical subsystem enables the identification of optimal spring characteristics for realistic operation conditions such as stochastic vibrations. With the overall transducer model, a combination of both subsystems connected to a simple electrical circuit, a virtual operation of the optimized vibration transducer excited by a measured random acceleration profile can be performed. It is shown that the optimization approach results in an appreciable increase of the converter performance

  15. Numerical Methods Application for Reinforced Concrete Elements-Theoretical Approach for Direct Stiffness Matrix Method

    Directory of Open Access Journals (Sweden)

    Sergiu Ciprian Catinas

    2015-07-01

    Full Text Available A detailed theoretical and practical investigation of the reinforced concrete elements is due to recent techniques and method that are implemented in the construction market. More over a theoretical study is a demand for a better and faster approach nowadays due to rapid development of the calculus technique. The paper above will present a study for implementing in a static calculus the direct stiffness matrix method in order capable to address phenomena related to different stages of loading, rapid change of cross section area and physical properties. The method is a demand due to the fact that in our days the FEM (Finite Element Method is the only alternative to such a calculus and FEM are considered as expensive methods from the time and calculus resources point of view. The main goal in such a method is to create the moment-curvature diagram in the cross section that is analyzed. The paper above will express some of the most important techniques and new ideas as well in order to create the moment curvature graphic in the cross sections considered.

  16. Experimental and numerical study of deposit formation in secondary side SG TSP by electrokinetic approach

    International Nuclear Information System (INIS)

    Guillodo, Michael; Foucault, Marc; Ryckelynck, Natacha; Chahma, Farah; Guingo, Mathieu; Mansour, Carine; Alos-Ramos, Olga; Corredera, Geraldine

    2012-09-01

    Corrosion products deposit formation observed in PWR steam generators (SGs) - related to SG free span fouling and SG clogging - is now reported since several years. SG clogging is a localized phenomenon observed between the leading edge of the Tube Support Plate (TSP) and SG tubing materials. Based on visual inspections, it was found that the gaps between SG tubing material and TSP at the lower part of the broached holes were getting progressively blocked. Therefore, for safe operation, most affected PWRs had to be operated at reduced power. TSP blockage was mainly observed for low-pH water chemistry conditioning, which directly depends on the operating water chemistry. The TSP blockage mechanism is complex due to the localized conditions in which flow pattern change, chemistry and electrochemical conditions are not well understood. Electrokinetic considerations could be pointed out to explain the coupling of chemistry, materials and thermohydraulic (T/H) conditions. In this frame AREVA and EDF have launched a long-term R and D program in order to understand the mechanisms driving the formation of SG clogging. This study based on parametric laboratory tests aims to assess the role of secondary water chemistry, material and T/H conditions on deposit formation. The experimental approach focused on electrokinetic measurements of metallic substrates and on the assessment of oxidation properties of materials in secondary side chemistry. An overall analysis of recent results is presented to address SG deposit formation in secondary water chemistry for various conditioning amines - morpholine, ethanolamine and dimethylamine. To complete the study, the experimental results have been correlated to CFD simulations of particle deposition, by means of stochastic Lagrangian models. These calculations have in particular reproduced correctly the location of the most important particle deposit (the leading edge of the test tube), and have stressed the influence of the

  17. Electrospun poly-l-lactide scaffold for the controlled and targeted delivery of a synthetically obtained Diclofenac prodrug to treat actinic keratosis.

    Science.gov (United States)

    Piccirillo, Germano; Bochicchio, Brigida; Pepe, Antonietta; Schenke-Layland, Katja; Hinderer, Svenja

    2017-04-01

    Actinic Keratosis' (AKs) are small skin lesions that are related to a prolonged sun-damage, which can develop into invasive squamous cell carcinoma (SCC) when left untreated. Effective, specific and well tolerable therapies to cure AKs are still of great interest. Diclofenac (DCF) is the current gold standard for the local treatment of AKs in terms of costs, effectiveness, side effects and tolerability. In this work, an electrospun polylactic acid (PLA) scaffold loaded with a synthetic DCF prodrug was developed and characterized. Specifically, the prodrug was successfully synthetized by binding DCF to a glycine residue via solid phase peptide synthesis (SPPS) and then incorporated in an electrospun PLA scaffold. The drug encapsulation was verified using multiphoton microscopy (MPM) and its scaffold release was spectrophotometrically monitored and confirmed with MPM. The scaffold was further characterized with scanning electron microscopy (SEM), tensile testing and contact angle measurements. Its biocompatibility was verified by performing a cell proliferation assay and compared to PLA scaffolds containing the same amount of DCF sodium salt (DCFONa). Finally, the effect of the electrospun scaffolds on human dermal fibroblasts (HDFs) morphology and metabolism was investigated by combining MPM with fluorescence lifetime imaging microscopy (FLIM). The obtained results suggest that the obtained scaffold could be suitable for the controlled and targeted delivery of the synthesized prodrug for the treatment of AKs. Electrospun scaffolds are of growing interest as materials for a controlled drug delivery. In this work, an electrospun polylactic acid scaffold containing a synthetically obtained Diclofenac prodrug is proposed as a novel substrate for the topical treatment of actinic keratosis. A controlled drug delivery targeted to the area of interest could enhance the efficacy of the therapy and favor the healing process. The prodrug was synthesized via solid phase

  18. Numerical results for near surface time domain electromagnetic exploration: a full waveform approach

    Science.gov (United States)

    Sun, H.; Li, K.; Li, X., Sr.; Liu, Y., Sr.; Wen, J., Sr.

    2015-12-01

    Time domain or Transient electromagnetic (TEM) survey including types with airborne, semi-airborne and ground play important roles in applicants such as geological surveys, ground water/aquifer assess [Meju et al., 2000; Cox et al., 2010], metal ore exploration [Yang and Oldenburg, 2012], prediction of water bearing structures in tunnels [Xue et al., 2007; Sun et al., 2012], UXO exploration [Pasion et al., 2007; Gasperikova et al., 2009] etc. The common practice is introducing a current into a transmitting (Tx) loop and acquire the induced electromagnetic field after the current is cut off [Zhdanov and Keller, 1994]. The current waveforms are different depending on instruments. Rectangle is the most widely used excitation current source especially in ground TEM. Triangle and half sine are commonly used in airborne and semi-airborne TEM investigation. In most instruments, only the off time responses are acquired and used in later analysis and data inversion. Very few airborne instruments acquire the on time and off time responses together. Although these systems acquire the on time data, they usually do not use them in the interpretation.This abstract shows a novel full waveform time domain electromagnetic method and our recent modeling results. The benefits comes from our new algorithm in modeling full waveform time domain electromagnetic problems. We introduced the current density into the Maxwell's equation as the transmitting source. This approach allows arbitrary waveforms, such as triangle, half-sine, trapezoidal waves or scatter record from equipment, being used in modeling. Here, we simulate the establishing and induced diffusion process of the electromagnetic field in the earth. The traditional time domain electromagnetic with pure secondary fields can also be extracted from our modeling results. The real time responses excited by a loop source can be calculated using the algorithm. We analyze the full time gates responses of homogeneous half space and two

  19. A numerical approach for assessing effects of shear on equivalent permeability and nonlinear flow characteristics of 2-D fracture networks

    Science.gov (United States)

    Liu, Richeng; Li, Bo; Jiang, Yujing; Yu, Liyuan

    2018-01-01

    Hydro-mechanical properties of rock fractures are core issues for many geoscience and geo-engineering practices. Previous experimental and numerical studies have revealed that shear processes could greatly enhance the permeability of single rock fractures, yet the shear effects on hydraulic properties of fractured rock masses have received little attention. In most previous fracture network models, single fractures are typically presumed to be formed by parallel plates and flow is presumed to obey the cubic law. However, related studies have suggested that the parallel plate model cannot realistically represent the surface characters of natural rock fractures, and the relationship between flow rate and pressure drop will no longer be linear at sufficiently large Reynolds numbers. In the present study, a numerical approach was established to assess the effects of shear on the hydraulic properties of 2-D discrete fracture networks (DFNs) in both linear and nonlinear regimes. DFNs considering fracture surface roughness and variation of aperture in space were generated using an originally developed code DFNGEN. Numerical simulations by solving Navier-Stokes equations were performed to simulate the fluid flow through these DFNs. A fracture that cuts through each model was sheared and by varying the shear and normal displacements, effects of shear on equivalent permeability and nonlinear flow characteristics of DFNs were estimated. The results show that the critical condition of quantifying the transition from a linear flow regime to a nonlinear flow regime is: 10-4 〈 J hydraulic gradient. When the fluid flow is in a linear regime (i.e., J reduce the equivalent permeability significantly in the orientation perpendicular to the sheared fracture as much as 53.86% when J = 1, shear displacement Ds = 7 mm, and normal displacement Dn = 1 mm. By fitting the calculated results, the mathematical expression for δ2 is established to help choose proper governing equations when

  20. The development of orally administrable gemcitabine prodrugs with D-enantiomer amino acids: enhanced membrane permeability and enzymatic stability.

    Science.gov (United States)

    Tsume, Yasuhiro; Incecayir, Tuba; Song, Xueqin; Hilfinger, John M; Amidon, Gordon L

    2014-04-01

    Gemcitabine prodrugs with D- and L-configuration amino acids were synthesized and their chemical stability in buffers, resistance to glycosidic bond metabolism, enzymatic activation, permeability in Caco-2 cells and mouse intestinal membrane, anti-proliferation activity in cancer cell were determined and compared to that of parent drug, gemcitabine. Prodrugs containing D-configuration amino acids were enzymatically more stable than ones with L-configuration amino acids. The activation of all gemcitabine prodrugs was 1.3-17.6-fold faster in cancer cell homogenate than their hydrolysis in buffer, suggesting enzymatic action. The enzymatic activation of amino acid monoester prodrugs containing D-configuration amino acids in cell homogenates was 2.2-10.9-fold slower than one of amino acid monoester prodrugs with L-configuration amino acids. All prodrugs exhibited enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase compared to parent gemcitabine. Gemcitabine prodrugs showed superior the effective permeability in mouse jejunum to gemcitabine. More importantly, the high plasma concentration of d-amino acid gemcitabine prodrugs was observed more than one of L-amino acid gemcitabine prodrugs. In general, the 5'-mono-amino acid monoester gemcitabine prodrugs exhibited higher permeability and uptake than their parent drug, gemcitabine. Cell proliferation assays in AsPC-1 pancreatic ductal cell line indicated that gemcitabine prodrugs were more potent than their parent drug, gemcitabine. The transport and enzymatic profiles of 5'-D-valyl-gemcitabine and 5'-D-phenylalanyl-gemcitabine suggest their potential for increased oral uptake and delayed enzymatic bioconversion as well as enhanced uptake and cytotoxic activity in cancer cells, would facilitate the development of oral dosage form for anti-cancer agents and, hence, improve the quality of life for the cancer patients. Copyright © 2014. Published by Elsevier B.V.

  1. Selection of suitable prodrug candidates for in vivo studies via in vitro studies; the correlation of prodrug stability in between cell culture homogenates and human tissue homogenates.

    Science.gov (United States)

    Tsume, Yasuhiro; Amidon, Gordon L

    2012-01-01

    To determine the correlations/discrepancies of drug stabilities between in the homogenates of human culture cells and of human tissues. Amino acid/dipeptide monoester prodrugs of floxuridine were chosen as the model drugs. The stabilities (half-lives) of floxuridine prodrugs in human tissues (pancreas, liver, and small intestine) homogenates were obtained and compared with ones in cell culture homogenates (AcPC-1, Capan-2, and Caco-2 cells) as well as human liver microsomes. The correlations of prodrug stability in human small bowel tissue homogenate vs. Caco-2 cell homogenate, human liver tissue homogenate vs. human liver microsomes, and human pancreatic tissue homogenate vs. pancreatic cell, AsPC-1 and Capan-2, homogenates were examined. The stabilities of floxuridine prodrugs in human small bowel homogenate exhibited the great correlation to ones in Caco-2 cell homogenate (slope = 1.0-1.3, r2 = 0.79-0.98). The stability of those prodrugs in human pancreas tissue homogenate also exhibited the good correlations to ones in AsPC-1 and Capan-2 cells homogenates (slope = 0.5-0.8, r2 = 0.58-0.79). However, the correlations of prodrug stabilities between in human liver tissue homogenates and in human liver microsomes were weaker than others (slope = 1.3-1.9, r2 = 0.07-0.24). The correlations of drug stabilities in cultured cell homogenates and in human tissue homogenates were compared. Those results exhibited wide range of correlations between in cell homogenate and in human tissue homogenate (r2 = 0.07 - 0.98). Those in vitro studies in cell homogenates would be good tools to predict drug stabilities in vivo and to select drug candidates for further developments. In the series of experiments, 5'-O-D-valyl-floxuridine and 5'-O-L-phenylalanyl-L-tyrosyl-floxuridine would be selected as candidates of oral drug targeting delivery for cancer chemotherapy due to their relatively good stabilities compared to other tested prodrugs.

  2. Design, Synthesis and Hydrolytic Behavior of Mutual Prodrugs of NSAIDs with Gabapentin Using Glycol Spacers

    Directory of Open Access Journals (Sweden)

    Hiba Najeh Alsaad

    2012-10-01

    Full Text Available The free –COOH present in NSAIDs is thought to be responsible for the GI irritation associated with all traditional NSAIDs. Exploitation of mutual prodrugs is an approach wherein the NSAID is covalently bounded to a second pharmacologically active carrier/drug with the ultimate aim of reducing the gastric irritation. In this study some NSAIDs were conjugated with gabapentin via ester bonds using glycol spacers with the expectation of reducing gastric adverse effects and obtaining synergistic analgesic effects. The kinetics of ester hydrolysis were studied in two different non enzymatic buffer solutions at pH 1.2 and 7.4, as well as in 80% human plasma using HPLC with chloroform -methanol as mobile phase. Compounds 9a–c with ethylene glycol spacers showed significant stability at buffer solutions with half lives ranging from about 8–25 h, while the underwent a reasonable plasma hydrolysis (49%–88% in 2 h. Compound 9d with a propylene glycol spacer shows a higher rate of enzymatic hydrolysis than the corresponding ethylene glycol compound 9c. The result of compounds 9a-c indicate that these compounds may be stable during their passage through the GIT until reaching the blood circulation.

  3. Ocular disposition of the hemiglutarate ester prodrug of ∆⁹-Tetrahydrocannabinol from various ophthalmic formulations.

    Science.gov (United States)

    Hingorani, Tushar; Adelli, Goutham R; Punyamurthula, Nagendra; Gul, Waseem; Elsohly, Mahmoud A; Repka, Michael A; Majumdar, Soumyajit

    2013-08-01

    The overall goal of this project is to enhance ocular delivery of ∆(9)-Tetrahydrocannabinol (THC) through the topical route. Solubility, stability and in vitro transcorneal permeability of the relatively hydrophilic hemiglutarate ester derivative, THC-HG, was studied in the presence of surfactants. The solutions were characterized with respect to micelle size, zeta potential and solution viscosity. In vivo studies were carried out in New Zealand albino rabbits. A previously reported promising THC-HG ion-pair formulation was also studied in vivo. Aqueous solubility and stability and in vitro transcorneal permeability of THC-HG was enhanced significantly in the presence of surfactants. THC levels in the ocular tissues (except cornea) were found to be below detection limits from mineral oil, surfactant or emulsion based formulations containing THC. In contrast, micellar and ion pair based THC-HG formulations produced significantly higher total THC concentrations in the anterior ocular chamber. In this study, although delivery of THC to the anterior chamber ocular tissues could be significantly increased through the prodrug and formulation approaches tested, further studies are needed to increase penetration to the back-of-the eye.

  4. Molecular Basis of Prodrug Activation by Human Valacyclovirase, an [alpha]-Amino Acid Ester Hydrolase

    Energy Technology Data Exchange (ETDEWEB)

    Lai, Longsheng; Xu, Zhaohui; Zhou, Jiahai; Lee, Kyung-Dall; Amidon, Gordon L. (Michigan)

    2008-07-08

    Chemical modification to improve biopharmaceutical properties, especially oral absorption and bioavailability, is a common strategy employed by pharmaceutical chemists. The approach often employs a simple structural modification and utilizes ubiquitous endogenous esterases as activation enzymes, although such enzymes are often unidentified. This report describes the crystal structure and specificity of a novel activating enzyme for valacyclovir and valganciclovir. Our structural insights show that human valacyclovirase has a unique binding mode and specificity for amino acid esters. Biochemical data demonstrate that the enzyme hydrolyzes esters of {alpha}-amino acids exclusively and displays a broad specificity spectrum for the aminoacyl moiety similar to tricorn-interacting aminopeptidase F1. Crystal structures of the enzyme, two mechanistic mutants, and a complex with a product analogue, when combined with biochemical analysis, reveal the key determinants for substrate recognition; that is, a flexible and mostly hydrophobic acyl pocket, a localized negative electrostatic potential, a large open leaving group-accommodating groove, and a pivotal acidic residue, Asp-123, after the nucleophile Ser-122. This is the first time that a residue immediately after the nucleophile has been found to have its side chain directed into the substrate binding pocket and play an essential role in substrate discrimination in serine hydrolases. These results as well as a phylogenetic analysis establish that the enzyme functions as a specific {alpha}-amino acid ester hydrolase. Valacyclovirase is a valuable target for amino acid ester prodrug-based oral drug delivery enhancement strategies.

  5. An Algorithm for the Numerical Solution of the Pseudo Compressible Navier-stokes Equations Based on the Experimenting Fields Approach

    KAUST Repository

    Salama, Amgad; Sun, Shuyu; Amin, Mohamed F. El

    2015-01-01

    In this work, the experimenting fields approach is applied to the numerical solution of the Navier-Stokes equation for incompressible viscous flow. In this work, the solution is sought for both the pressure and velocity fields in the same time. Apparently, the correct velocity and pressure fields satisfy the governing equations and the boundary conditions. In this technique a set of predefined fields are introduced to the governing equations and the residues are calculated. The flow according to these fields will not satisfy the governing equations and the boundary conditions. However, the residues are used to construct the matrix of coefficients. Although, in this setup it seems trivial constructing the global matrix of coefficients, in other setups it can be quite involved. This technique separates the solver routine from the physics routines and therefore makes easy the coding and debugging procedures. We compare with few examples that demonstrate the capability of this technique.

  6. A study on the unsteady flow of two immiscible micropolar and Newtonian fluids through a horizontal channel: A numerical approach

    Science.gov (United States)

    Devakar, M.; Raje, Ankush

    2018-05-01

    The unsteady flow of two immiscible micropolar and Newtonian fluids through a horizontal channel is considered. In addition to the classical no-slip and hyper-stick conditions at the boundary, it is assumed that the fluid velocities and shear stresses are continuous across the fluid-fluid interface. Three cases for the applied pressure gradient are considered to study the problem: one with constant pressure gradient and the other two cases with time-dependent pressure gradients, viz. periodic and decaying pressure gradient. The Crank-Nicolson approach has been used to obtain numerical solutions for fluid velocity and microrotation for diverse sets of fluid parameters. The nature of fluid velocities and microrotation with various values of pressure gradient, Reynolds number, ratio of viscosities, micropolarity parameter and time is illustrated through graphs. It has been observed that micropolarity parameter and ratio of viscosities reduce the fluid velocities.

  7. An Algorithm for the Numerical Solution of the Pseudo Compressible Navier-stokes Equations Based on the Experimenting Fields Approach

    KAUST Repository

    Salama, Amgad

    2015-06-01

    In this work, the experimenting fields approach is applied to the numerical solution of the Navier-Stokes equation for incompressible viscous flow. In this work, the solution is sought for both the pressure and velocity fields in the same time. Apparently, the correct velocity and pressure fields satisfy the governing equations and the boundary conditions. In this technique a set of predefined fields are introduced to the governing equations and the residues are calculated. The flow according to these fields will not satisfy the governing equations and the boundary conditions. However, the residues are used to construct the matrix of coefficients. Although, in this setup it seems trivial constructing the global matrix of coefficients, in other setups it can be quite involved. This technique separates the solver routine from the physics routines and therefore makes easy the coding and debugging procedures. We compare with few examples that demonstrate the capability of this technique.

  8. Quantitative assessment of key parameters in qualitative vulnerability methods applied in karst systems based on an integrated numerical modelling approach

    Science.gov (United States)

    Doummar, Joanna; Kassem, Assaad

    2017-04-01

    In the framework of a three-year PEER (USAID/NSF) funded project, flow in a Karst system in Lebanon (Assal) dominated by snow and semi arid conditions was simulated and successfully calibrated using an integrated numerical model (MIKE-She 2016) based on high resolution input data and detailed catchment characterization. Point source infiltration and fast flow pathways were simulated by a bypass function and a high conductive lens respectively. The approach consisted of identifying all the factors used in qualitative vulnerability methods (COP, EPIK, PI, DRASTIC, GOD) applied in karst systems and to assess their influence on recharge signals in the different hydrological karst compartments (Atmosphere, Unsaturated zone and Saturated zone) based on the integrated numerical model. These parameters are usually attributed different weights according to their estimated impact on Groundwater vulnerability. The aim of this work is to quantify the importance of each of these parameters and outline parameters that are not accounted for in standard methods, but that might play a role in the vulnerability of a system. The spatial distribution of the detailed evapotranspiration, infiltration, and recharge signals from atmosphere to unsaturated zone to saturated zone was compared and contrasted among different surface settings and under varying flow conditions (e.g., in varying slopes, land cover, precipitation intensity, and soil properties as well point source infiltration). Furthermore a sensitivity analysis of individual or coupled major parameters allows quantifying their impact on recharge and indirectly on vulnerability. The preliminary analysis yields a new methodology that accounts for most of the factors influencing vulnerability while refining the weights attributed to each one of them, based on a quantitative approach.

  9. A Combined Remote Sensing-Numerical Modelling Approach to the Stability Analysis of Delabole Slate Quarry, Cornwall, UK

    Science.gov (United States)

    Havaej, Mohsen; Coggan, John; Stead, Doug; Elmo, Davide

    2016-04-01

    Rock slope geometry and discontinuity properties are among the most important factors in realistic rock slope analysis yet they are often oversimplified in numerical simulations. This is primarily due to the difficulties in obtaining accurate structural and geometrical data as well as the stochastic representation of discontinuities. Recent improvements in both digital data acquisition and incorporation of discrete fracture network data into numerical modelling software have provided better tools to capture rock mass characteristics, slope geometries and digital terrain models allowing more effective modelling of rock slopes. Advantages of using improved data acquisition technology include safer and faster data collection, greater areal coverage, and accurate data geo-referencing far exceed limitations due to orientation bias and occlusion. A key benefit of a detailed point cloud dataset is the ability to measure and evaluate discontinuity characteristics such as orientation, spacing/intensity and persistence. This data can be used to develop a discrete fracture network which can be imported into the numerical simulations to study the influence of the stochastic nature of the discontinuities on the failure mechanism. We demonstrate the application of digital terrestrial photogrammetry in discontinuity characterization and distinct element simulations within a slate quarry. An accurately geo-referenced photogrammetry model is used to derive the slope geometry and to characterize geological structures. We first show how a discontinuity dataset, obtained from a photogrammetry model can be used to characterize discontinuities and to develop discrete fracture networks. A deterministic three-dimensional distinct element model is then used to investigate the effect of some key input parameters (friction angle, spacing and persistence) on the stability of the quarry slope model. Finally, adopting a stochastic approach, discrete fracture networks are used as input for 3D

  10. Preparation, characterization and in vitro evaluation of a new nucleotide analogue prodrug cyclodextrin inclusion complexes.

    Science.gov (United States)

    Diab, Roudayna; Jordheim, Lars P; Degobert, Ghania; Peyrottes, Suzanne; Périgaud, Christian; Dumontet, Charles; Fessi, Hatem

    2009-01-01

    Bis(tbutyl-S-acyl-2-thioethyl)-cytidine monophosophate is a new cytotoxic mononucleotide prodrug which have been developed to reverse the cellular resistance to nucleoside analogues. Unfortunately, its in vivo utilisation was hampered by its poor water solubility, raising the need of a molecular vector capable to mask its physicochemical characteristics although without affecting its cytotoxic activity. Hydroxypropyl-beta-cyclodextrin was used to prepare the prodrug inclusion complexes, allowing it to be solubilized in water and hence to be used for in vitro and in vivo experiments. A molar ratio of the cyclodextrin: prodrug of 3 was sufficient to obtain complete solubilization of the prodrug. The inclusion complex was characterized by differential scanning calorimetry, which revealed the disappearance of the melting peak of the prodrug suggesting the formation of inclusion complex. Proton Nuclear Magnetic Resonance spectroscopy provided a definitive proof of the inclusion complex formation, which was evidenced by the large chemical shift displacements observed for protons located in the interior of the hydrophobic cyclodextrin cavity. The complex retained its cytotoxic activity as shown by in vitro cell survival assays on murine leukemia cells. These results provided a basis for potential therapeutic applications of co-formulation of this new nucleotide analogue with hydroxypropyl-beta-CD in cancer therapy.

  11. Formulation and evaluation of co-prodrug of flurbiprofen and methocarbamol

    Directory of Open Access Journals (Sweden)

    Neela Bhatia

    2016-06-01

    Full Text Available The current work envisages synthesis of an ester prodrug of flurbiprofen whereby its carboxylic group was condensed with a skeletal muscle relaxant methocarbamol, with the aim of synergistic activity of two drugs, avoid flurbiprofen mediated gastro-intestinal damage and minimize the ulceration tendency of flurbiprofen. The synthesized prodrug was characterized and confirmed by physicochemical and spectroscopic studies. Solubility and partition coefficient studies indicated an increased lipophilicity and thus better suitability for oral administration than the parent drugs and the protein binding studies revealed a low protein binding capacity of the mutual prodrug. Subsequently, in-vitro hydrolysis was studied in different pH, simulated gastric fluid, simulated intestinal fluid and plasma and quantitative evaluation was performed by high performance liquid chromatography. It was found that the prodrug remained unhydrolyzed in the stomach after absorption however, underwent rapid cleavage by the esterases in blood to give the parent drug. Furthermore, the mutual ester prodrug was evaluated for its anti-inflammatory, analgesic, skeletal muscle relaxation, ulcerogenic and total acid content activity and was found to possess comparable activity with that of the parent drugs. Microscopic structures of the stomach tissues revealed significant reduction in gastric ulcer formation of mice gastric mucosa as compared to parent carboxylic acid drug.

  12. Delivery of Gemcitabine Prodrugs Employing Mesoporous Silica Nanoparticles

    Directory of Open Access Journals (Sweden)

    Alessio Malfanti

    2016-04-01

    Full Text Available In this paper, mesoporous silica nanoparticles (MSNs were studied as vehicles for the delivery of the antitumoral drug gemcitabine (GEM and of its 4-(N-acyl derivatives, (4-(N-valeroyl-(C5GEM, 4-(N-lauroyl-(C12GEM and 4-(N-stearoyl-gemcitabine (C18GEM. The loading of the GEM lipophilic prodrugs on MSNs was explored with the aim to obtain both a physical and a chemical protection of GEM from rapid plasmatic metabolization. For this purpose, MSNs as such or with grafted aminopropyl and carboxyethyl groups were prepared and characterized. Then, their different drug loading capacity in relation to the nature of the functional group was evaluated. In our experimental conditions, GEM was not loaded in any MSNs, while C12GEM was the most efficiently encapsulated and employed for further evaluation. The results showed that loading capacity increased with the presence of functional groups on the nanoparticles; similarly, the presence of functional groups on MSNs’ surface influenced the drug release profile. Finally, the cytotoxicity of the different preparations was evaluated and data showed that C12GEM loaded MSNs are less cytotoxic than the free drug with an activity that increased with the incubating time, indicating that all these systems are able to release the drug in a controlled manner. Altogether, the results demonstrate that these MSNs could be an interesting system for the delivery of anticancer drugs.

  13. Slow self-activation enhances the potency of viridin prodrugs.

    Science.gov (United States)

    Blois, Joseph; Yuan, Hushan; Smith, Adam; Pacold, Michael E; Weissleder, Ralph; Cantley, Lewis C; Josephson, Lee

    2008-08-14

    When the viridin wortmannin (Wm) is modified by reaction with certain nucleophiles at the C20 position, the compounds obtained exhibit an improved antiproliferative activity even though a covalent reaction between C20 and a lysine in the active site of PI3 kinase is essential to Wm's ability to inhibit this enzyme. Here we show that this improved potency results from an intramolecular attack by the C6 hydroxyl group that slowly converts these inactive prodrugs to the active species Wm over the 48 h duration of the antiproliferative assay. Our results provide a guide for selecting Wm-like compounds to maximize kinase inhibition with the variety of protocols used to assess the role of PI3 kinase in biological systems, or for achieving optimal therapeutic effects in vivo . In addition, the slow self-activation of WmC20 derivatives provides a mechanism that can be exploited to obtain kinase inhibitors endowed with physical and pharmacokinetic properties far different from man-made kinase inhibitors because they do not bind to kinase active sites.

  14. Identification of a Potent Phosphoinositide 3-Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs.

    Science.gov (United States)

    Pirali, Tracey; Ciraolo, Elisa; Aprile, Silvio; Massarotti, Alberto; Berndt, Alex; Griglio, Alessia; Serafini, Marta; Mercalli, Valentina; Landoni, Clarissa; Campa, Carlo Cosimo; Margaria, Jean Piero; Silva, Rangel L; Grosa, Giorgio; Sorba, Giovanni; Williams, Roger; Hirsch, Emilio; Tron, Gian Cesare

    2017-09-21

    Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so-far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan-PI3K inhibitor. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Flurbiprofen–antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling

    Science.gov (United States)

    Ashraf, Zaman; Alamgeer; Kanwal, Munazza; Hassan, Mubashir; Abdullah, Sahar; Waheed, Mamuna; Ahsan, Haseeb; Kim, Song Ja

    2016-01-01

    Flurbiprofen–antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (–COOH) was temporarily masked by esterification with phenolic –OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (Pflurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer’s yeast-induced pyrexia model, and significant (Pflurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities with reduced GI adverse effects than the parent drug. PMID:27555750

  16. Flurbiprofen-antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling.

    Science.gov (United States)

    Ashraf, Zaman; Alamgeer; Kanwal, Munazza; Hassan, Mubashir; Abdullah, Sahar; Waheed, Mamuna; Ahsan, Haseeb; Kim, Song Ja

    2016-01-01

    Flurbiprofen-antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (-COOH) was temporarily masked by esterification with phenolic -OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (Pflurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer's yeast-induced pyrexia model, and significant (Pflurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities with reduced GI adverse effects than the parent drug.

  17. Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts

    NARCIS (Netherlands)

    Houba, PHJ; Boven, E; van der Meulen-Muileman, IH; Leenders, RGG; Scheeren, JW; Pinedo, HM; Haisma, HJ

    1999-01-01

    N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-beta-glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug

  18. Synthesis, In Vitro and In Vivo Evaluation of the N-ethoxycarbonylmorpholine Ester of Diclofenac as a Prodrug

    Directory of Open Access Journals (Sweden)

    Jamal A. Jilani

    2014-04-01

    Full Text Available The N-ethoxycarbonylmorpholine moiety was evaluated as a novel prodrug moiety for carboxylic acid containing drugs represented by diclofenac (1. Compound 2, the N-ethoxycarbonylmorpholine ester of diclofenac was synthesized and evaluated as a potential prodrug. The stability of the synthesized prodrug was evaluated in solutions of pH 1 and 7.4, and in plasma. The ester’s half lives were found to be 8 h, 47 h and 21 min in pH 1, pH 7.4 and plasma, respectively. Equimolar doses of diclofenac sodium and its synthesized prodrug were administered orally to a group of rabbits in a crossover study to evaluate their pharmacokinetic parameters. The prodrug 2 shows a similar rate and extent of absorption as the parent drug (1. The ulcerogenicity of the prepared prodrug was evaluated and compared with the parent drug. The prodrug showed less ulcerogenicity as detected by fewer number and smaller size of ulcers. In conclusion, the newly synthesized N-ethoxycarbonylmorpholine ester of diclofenac prodrug showed appropriate stability properties at different pHs, similar pharmacokinetic profile, and much less ulcerogenecity at the GIT compared to the parent drug diclofenac.

  19. A conservative, thermodynamically consistent numerical approach for low Mach number combustion. Part I: Single-level integration

    Science.gov (United States)

    Nonaka, Andrew; Day, Marcus S.; Bell, John B.

    2018-01-01

    We present a numerical approach for low Mach number combustion that conserves both mass and energy while remaining on the equation of state to a desired tolerance. We present both unconfined and confined cases, where in the latter the ambient pressure changes over time. Our overall scheme is a projection method for the velocity coupled to a multi-implicit spectral deferred corrections (SDC) approach to integrate the mass and energy equations. The iterative nature of SDC methods allows us to incorporate a series of pressure discrepancy corrections naturally that lead to additional mass and energy influx/outflux in each finite volume cell in order to satisfy the equation of state. The method is second order, and satisfies the equation of state to a desired tolerance with increasing iterations. Motivated by experimental results, we test our algorithm on hydrogen flames with detailed kinetics. We examine the morphology of thermodiffusively unstable cylindrical premixed flames in high-pressure environments for confined and unconfined cases. We also demonstrate that our algorithm maintains the equation of state for premixed methane flames and non-premixed dimethyl ether jet flames.

  20. Click polymerization for the synthesis of reduction-responsive polymeric prodrug

    Science.gov (United States)

    Zhang, Xiaojin; Wang, Hongquan; Dai, Yu

    2018-05-01

    Click polymerization is a powerful polymerization technique for the construction of new macromolecules with well-defined structures and multifaceted functionalities. Here, we synthesize reduction-responsive polymeric prodrug PEG- b-(PSS- g-MTX)- b-PEG containing disulfide bonds and pendant methotrexate (MTX) via two-step click polymerization followed by conjugating MTX to pendant hydroxyl. MTX content in polymeric prodrug is 13.5%. Polymeric prodrug is able to form polymeric micelles by self-assembly in aqueous solution. Polymeric micelles are spherical nanoparticles with tens of nanometers in size. Of note, polymeric micelles are reduction-responsive due to disulfide bonds in the backbone of PEG- b-(PSS- g-MTX)- b-PEG and could release pendant drugs in the presence of the reducing agents such as dl-dithiothreitol (DTT).

  1. N,N'-dihydroxyamidines: a new prodrug principle to improve the oral bioavailability of amidines.

    Science.gov (United States)

    Reeh, Christiane; Wundt, Judith; Clement, Bernd

    2007-12-27

    N, N'-dihydroxybenzamdine represents a model compound for a new prodrug principle to improve the oral bioavailability of drugs containing amidine functions. The activation of the prodrug could be demonstrated in vitro by porcine and human subcellular enzyme fractions, the mitochondrial benzamidoxime reducing system, and porcine hepatocytes. In vivo, the bioavailability of benzamidine after oral application of N, N'-dihydroxybenzamidine was about 91% and exceeded that of benzamidine after oral application of benzamidoxime, being about 74% (Liu, L.; Ling, Y.; Havel, C.; Bashnick, L.; Young, W.; Rai, R.; Vijaykumar, D.; Riggs, J. R.; Ton, T.; Shaghafi, M.; Graupe, D.; Mordenti, J.; Sukbuntherng, J. Species comparison of in vitro and in vivo conversion of five N-hydroxyamidine prodrugs of fVIIA inhibitors to their corresponding active amidines. Presented at the 13th North America ISSX Meeting, Maui, HI, 2005).

  2. Lipid conjugated prodrugs for enzyme-triggered liposomal drug delivery to tumors

    DEFF Research Database (Denmark)

    Clausen, Mads Hartvig

    2011-01-01

    For some time we have been developing novel enzyme-triggered prodrugs for drug delivery targeting cancer. The liposomal prodrugs take advantage of the EPR effect to localize to tumors and of the local over-expression of secretory phospholipase A2 in tumors. Compared to conventional liposomal drug...... delivery systems, our prodrug-lipid conjugates have two main advantages: 1) the drugs are covalently linked to the lipids and thus leakage is circumvented and 2) the lipophilic bilayer of the formulated liposomes effectively shields the drugs from the aqueous environment in vivo. Consequently, the strategy...... targeting nuclear receptors and structural proteins. The presentation will highlight various strategies and recent progress towards improved systems, including chemical synthesis, enzyme activity and cytotoxicity....

  3. A numerical approach for the study of large sodium spray fires and its application for SPX1

    International Nuclear Information System (INIS)

    Varet, T.; Leroy, B.; Barthez, M.; Malet, J.C.

    1996-01-01

    For the original design of SUPER-PHENIX, only pool fires were analysed for secondary sodium because these were thought to be the most likely. However, after the sodium spray fire at the solar plant of ALMERIA, an analysis of the consequences of secondary spray fire was undertaken. According to the French Safety Authority, the most penalizing cases of sodium leak and fire must be taken into account for each type of consequences, up to the complete rupture of a main secondary pipe. The experimental data available were mainly based on sodium flowrates in the range of ten kilograms per second, which are far below the leak flowrates obtained in case of a complete rupture of a main secondary pipe, i.e. several tons of sodium per second during a short time interval; moreover, it was obviously not possible to perform sodium tests with such high flowrate conditions. Consequently a complete methodology for the prediction of the behaviour of large sodium spray fires has been developed: the two-dimensional code PULSAR, which solves the two phase flow Navier-Stokes equations with source terms of mass and energy, is first used to evaluate the physical behaviour of a spray of sodium droplets in a cell in diverse conditions and thus to determine the burning rate. This last value is then used as data in the FEUMIX code in which other phenomena such as the dynamic response of pressure relief systems are described, in order to determine the pressure transient in the cell. This approach has been successfully tested using the experimental data available from past and recent tests, particularly the high flowrates tests IGNA 3602 and IGNA 3604. This numerical approach has been applied to the analysis of the consequences of postulated large sodium leaks in SUPER-PHENIX and allowed us to justify the hypotheses used to design the protective measures implemented on the plant, and thus the demonstration of safety with regard to large sodium leaks. (author)

  4. Measuring multi-joint stiffness during single movements: numerical validation of a novel time-frequency approach.

    Science.gov (United States)

    Piovesan, Davide; Pierobon, Alberto; DiZio, Paul; Lackner, James R

    2012-01-01

    This study presents and validates a Time-Frequency technique for measuring 2-dimensional multijoint arm stiffness throughout a single planar movement as well as during static posture. It is proposed as an alternative to current regressive methods which require numerous repetitions to obtain average stiffness on a small segment of the hand trajectory. The method is based on the analysis of the reassigned spectrogram of the arm's response to impulsive perturbations and can estimate arm stiffness on a trial-by-trial basis. Analytic and empirical methods are first derived and tested through modal analysis on synthetic data. The technique's accuracy and robustness are assessed by modeling the estimation of stiffness time profiles changing at different rates and affected by different noise levels. Our method obtains results comparable with two well-known regressive techniques. We also test how the technique can identify the viscoelastic component of non-linear and higher than second order systems with a non-parametrical approach. The technique proposed here is very impervious to noise and can be used easily for both postural and movement tasks. Estimations of stiffness profiles are possible with only one perturbation, making our method a useful tool for estimating limb stiffness during motor learning and adaptation tasks, and for understanding the modulation of stiffness in individuals with neurodegenerative diseases.

  5. Measuring multi-joint stiffness during single movements: numerical validation of a novel time-frequency approach.

    Directory of Open Access Journals (Sweden)

    Davide Piovesan

    Full Text Available This study presents and validates a Time-Frequency technique for measuring 2-dimensional multijoint arm stiffness throughout a single planar movement as well as during static posture. It is proposed as an alternative to current regressive methods which require numerous repetitions to obtain average stiffness on a small segment of the hand trajectory. The method is based on the analysis of the reassigned spectrogram of the arm's response to impulsive perturbations and can estimate arm stiffness on a trial-by-trial basis. Analytic and empirical methods are first derived and tested through modal analysis on synthetic data. The technique's accuracy and robustness are assessed by modeling the estimation of stiffness time profiles changing at different rates and affected by different noise levels. Our method obtains results comparable with two well-known regressive techniques. We also test how the technique can identify the viscoelastic component of non-linear and higher than second order systems with a non-parametrical approach. The technique proposed here is very impervious to noise and can be used easily for both postural and movement tasks. Estimations of stiffness profiles are possible with only one perturbation, making our method a useful tool for estimating limb stiffness during motor learning and adaptation tasks, and for understanding the modulation of stiffness in individuals with neurodegenerative diseases.

  6. Numerical Evaluation and Optimization of Multiple Hydraulically Fractured Parameters Using a Flow-Stress-Damage Coupled Approach

    Directory of Open Access Journals (Sweden)

    Yu Wang

    2016-04-01

    Full Text Available Multiple-factor analysis and optimization play a critical role in the the ability to maximizethe stimulated reservoir volume (SRV and the success of economic shale gas production. In this paper, taking the typical continental naturally fractured silty laminae shale in China as anexample, response surface methodology (RSM was employed to optimize multiple hydraulic fracturing parameters to maximize the stimulated area in combination with numerical modeling based on the coupled flow-stress-damage (FSD approach. This paper demonstrates hydraulic fracturing effectiveness by defining two indicesnamelythe stimulated reservoir area (SRA and stimulated silty laminae area (SLA. Seven uncertain parameters, such as laminae thickness, spacing, dip angle, cohesion, internal friction angle (IFA, in situ stress difference (SD, and an operational parameter-injection rate (IR with a reasonable range based on silty Laminae Shale, Southeastern Ordos Basin, are used to fit a response of SRA and SLA as the objective function, and finally identity the optimum design under the parameters based on simultaneously maximizingSRA and SLA. In addition, asensitivity analysis of the influential factors is conducted for SRA and SLA. The aim of the study is to improve the artificial ability to control the fracturing network by means of multi-parameteroptimization. This work promises to provide insights into the effective exploitation of unconventional shale gas reservoirs via optimization of the fracturing design for continental shale, Southeastern Ordos Basin, China.

  7. A least-squares minimisation approach to depth determination from numerical second horizontal self-potential anomalies

    Science.gov (United States)

    Abdelrahman, El-Sayed Mohamed; Soliman, Khalid; Essa, Khalid Sayed; Abo-Ezz, Eid Ragab; El-Araby, Tarek Mohamed

    2009-06-01

    This paper develops a least-squares minimisation approach to determine the depth of a buried structure from numerical second horizontal derivative anomalies obtained from self-potential (SP) data using filters of successive window lengths. The method is based on using a relationship between the depth and a combination of observations at symmetric points with respect to the coordinate of the projection of the centre of the source in the plane of the measurement points with a free parameter (graticule spacing). The problem of depth determination from second derivative SP anomalies has been transformed into the problem of finding a solution to a non-linear equation of the form f(z)=0. Formulas have been derived for horizontal cylinders, spheres, and vertical cylinders. Procedures are also formulated to determine the electric dipole moment and the polarization angle. The proposed method was tested on synthetic noisy and real SP data. In the case of the synthetic data, the least-squares method determined the correct depths of the sources. In the case of practical data (SP anomalies over a sulfide ore deposit, Sariyer, Turkey and over a Malachite Mine, Jefferson County, Colorado, USA), the estimated depths of the buried structures are in good agreement with the results obtained from drilling and surface geology.

  8. Groundwater-surface water interactions across scales in a boreal landscape investigated using a numerical modelling approach

    Science.gov (United States)

    Jutebring Sterte, Elin; Johansson, Emma; Sjöberg, Ylva; Huseby Karlsen, Reinert; Laudon, Hjalmar

    2018-05-01

    Groundwater and surface-water interactions are regulated by catchment characteristics and complex inter- and intra-annual variations in climatic conditions that are not yet fully understood. Our objective was to investigate the influence of catchment characteristics and freeze-thaw processes on surface and groundwater interactions in a boreal landscape, the Krycklan catchment in Sweden. We used a numerical modelling approach and sub-catchment evaluation method to identify and evaluate fundamental catchment characteristics and processes. The model reproduced observed stream discharge patterns of the 14 sub-catchments and the dynamics of the 15 groundwater wells with an average accumulated discharge error of 1% (15% standard deviation) and an average groundwater-level mean error of 0.1 m (0.23 m standard deviation). We show how peatland characteristics dampen the effect of intense rain, and how soil freeze-thaw processes regulate surface and groundwater partitioning during snowmelt. With these results, we demonstrate the importance of defining, understanding and quantifying the role of landscape heterogeneity and sub-catchment characteristics for accurately representing catchment hydrological functioning.

  9. Abrogation of Antibody-Induced Arthritis in Mice by a Self-Activating Viridin Prodrug and Association With Impaired Neutrophil and Endothelial Cell Function

    Science.gov (United States)

    Stangenberg, Lars; Ellson, Chris; Cortez-Retamozo, Virna; Ortiz-Lopez, Adriana; Yuan, Hushan; Blois, Joseph; Smith, Ralph A.; Yaffe, Michael B.; Weissleder, Ralph; Benoist, Christophe; Mathis, Diane; Josephson, Lee; Mahmood, Umar

    2009-01-01

    Objective To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis. Methods The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin–selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil–endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay. Results SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor α was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration. Conclusion A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions. PMID:19644878

  10. Effective gene silencing activity of prodrug-type 2'-O-methyldithiomethyl siRNA compared with non-prodrug-type 2'-O-methyl siRNA.

    Science.gov (United States)

    Hayashi, Junsuke; Nishigaki, Misa; Ochi, Yosuke; Wada, Shun-Ichi; Wada, Fumito; Nakagawa, Osamu; Obika, Satoshi; Harada-Shiba, Mariko; Urata, Hidehito

    2018-07-01

    Small interfering RNAs (siRNAs) are an active agent to induce gene silencing and they have been studied for becoming a biological and therapeutic tool. Various 2'-O-modified RNAs have been extensively studied to improve the nuclease resistance. However, the 2'-O-modified siRNA activities were often decreased by modification, since the bulky 2'-O-modifications inhibit to form a RNA-induced silencing complex (RISC). We developed novel prodrug-type 2'-O-methyldithiomethyl (MDTM) siRNA, which is converted into natural siRNA in an intracellular reducing environment. Prodrug-type 2'-O-MDTM siRNAs modified at the 5'-end side including 5'-end nucleotide and the seed region of the antisense strand exhibited much stronger gene silencing effect than non-prodrug-type 2'-O-methyl (2'-O-Me) siRNAs. Furthermore, the resistances for nuclease digestion of siRNAs were actually enhanced by 2'-O-MDTM modifications. Our results indicate that 2'-O-MDTM modifications improve the stability of siRNA in serum and they are able to be introduced at any positions of siRNA. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Click and Release: A Chemical Strategy toward Developing Gasotransmitter Prodrugs by Using an Intramolecular Diels-Alder Reaction.

    Science.gov (United States)

    Ji, Xingyue; Zhou, Cheng; Ji, Kaili; Aghoghovbia, Robert E; Pan, Zhixiang; Chittavong, Vayou; Ke, Bowen; Wang, Binghe

    2016-12-19

    Prodrug strategies have been proven to be a very effective way of addressing delivery problems. Much of the chemistry in prodrug development relies on the ability to mask an appropriate functional group, which can be removed under appropriate conditions. However, developing organic prodrugs of gasotransmitters represent unique challenges. This is especially true with carbon monoxide, which does not have an easy "handle" for bioreversible derivatization. By taking advantage of an intramolecular Diels-Alder reaction, we have developed a prodrug strategy for preparations of organic CO prodrugs that are stable during synthesis and storage, and yet readily release CO with tunable release rates under near physiological conditions. The effectiveness of the CO prodrug system in delivering a sufficient quantity of CO for possible therapeutic applications has been studied using a cell culture anti-inflammatory assay and a colitis animal model. These studies fully demonstrate the proof of concept, and lay a strong foundation for further medicinal chemistry work in developing organic CO prodrugs. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Selective transfer of a lipophilic prodrug of 5-fluorodeoxyuridine from immunoliposomes to colon cancer cells

    NARCIS (Netherlands)

    Koning, GA; Morselt, HWM; Donga, J; Gorter, A; Allen, TM; Zalipsky, S; Kamps, JAAM; Scherphof, GL

    1999-01-01

    A monoclonal antibody against the rat colon carcinoma CC531 was covalently coupled to liposomes containing a dipalmitoylated derivative of the anticancer drug FUdR as a prodrug in their bilayers. We investigated the in vitro interaction of these liposomes with CC531 target cells and the mechanism by

  13. Prodrugs available on the Brazilian pharmaceutical market and their corresponding bioactivation pathways

    Directory of Open Access Journals (Sweden)

    Roberto Parise Filho

    2010-09-01

    Full Text Available The aim of this paper was to emphasize the importance of prodrug design to therapy, by examining examples available on the Brazilian pharmaceutical market. The principles of prodrug design are briefly discussed herein. Examples of prodrugs from many important therapeutic classes are shown and their advantages relative to the drugs they are derived from are also discussed. Considering the importance of these therapeutic classes, from both therapy and economic standpoints, prodrug design is a very valuable aspect in the research of new drugs and for the pharmaceutical industry as a whole.O objetivo do trabalho foi ressaltar a importância do planejamento de pró-fármacos para a terapia, por meio de exemplos disponíveis no mercado farmacêutico brasileiro. Os princípios da latenciação são sucintamente discutidos. Apresentam-se exemplos de pró-fármacos de muitas classes terapêuticas importantes e as vantagens relativas aos fármacos dos quais derivam são, também, discutidas. Considerando-se a importância dessas classes terapêuticas, tanto do aspecto terapêutico quanto do econômico, o planejamento de pró-fármacos representa aspecto de grande valor na busca de novos fármacos e na indústria farmacêutica como um todo.

  14. Clinical Advances of Hypoxia-Activated Prodrugs in Combination With Radiation Therapy.

    Science.gov (United States)

    Mistry, Ishna N; Thomas, Matthew; Calder, Ewen D D; Conway, Stuart J; Hammond, Ester M

    2017-08-01

    With the increasing incidence of cancer worldwide, the need for specific, effective therapies is ever more urgent. One example of targeted cancer therapeutics is hypoxia-activated prodrugs (HAPs), also known as bioreductive prodrugs. These prodrugs are inactive in cells with normal oxygen levels but in hypoxic cells (with low oxygen levels) undergo chemical reduction to the active compound. Hypoxia is a common feature of solid tumors and is associated with a more aggressive phenotype and resistance to all modes of therapy. Therefore, the combination of radiation therapy and bioreductive drugs presents an attractive opportunity for synergistic effects, because the HAP targets the radiation-resistant hypoxic cells. Hypoxia-activated prodrugs have typically been precursors of DNA-damaging agents, but a new generation of molecularly targeted HAPs is emerging. By targeting proteins associated with tumorigenesis and survival, these compounds may result in greater selectivity over healthy tissue. We review the clinical progress of HAPs as adjuncts to radiation therapy and conclude that the use of HAPs alongside radiation is vastly underexplored at the clinical level. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  15. Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue.

    Science.gov (United States)

    Lupia, R H; Ferencz, N; Lertora, J J; Aggarwal, S K; George, W J; Agrawal, K C

    1993-04-01

    The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and IAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system.

  16. Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs

    Czech Academy of Sciences Publication Activity Database

    Daum, S.; Reshetnikov, M.S.V.; Šíša, Miroslav; Dumych, T.; Lootsik, M. D.; Bilyy, R.; Bila, E.; Janko, C.; Alexiou, C.; Herrmann, M.; Sellner, L.; Mokhir, A.

    2017-01-01

    Roč. 56, č. 49 (2017), s. 15545-15549 ISSN 1433-7851 Institutional support: RVO:61389030 Keywords : aminoferrocene * cancer * lysosomes * prodrugs * reactive oxygen species Subject RIV: ED - Physiology OBOR OECD: Organic chemistry Impact factor: 11.994, year: 2016

  17. Chemotherapeutic potential of diazeniumdiolate-based aspirin prodrugs in breast cancer.

    Science.gov (United States)

    Basudhar, Debashree; Cheng, Robert C; Bharadwaj, Gaurav; Ridnour, Lisa A; Wink, David A; Miranda, Katrina M

    2015-06-01

    Diazeniumdiolate-based aspirin prodrugs have previously been shown to retain the anti-inflammatory properties of aspirin while protecting against the common side effect of stomach ulceration. Initial analysis of two new prodrugs of aspirin that also release either nitroxyl (HNO) or nitric oxide (NO) demonstrated increased cytotoxicity toward human lung carcinoma cells compared to either aspirin or the parent nitrogen oxide donor. In addition, cytotoxicity was significantly lower in endothelial cells, suggesting cancer-specific sensitivity. To assess the chemotherapeutic potential of these new prodrugs in treatment of breast cancer, we studied their effect both in cultured cells and in a nude mouse model. Both prodrugs reduced growth of breast adenocarcinoma cells more effectively than the parent compounds while not being appreciably cytotoxic in a related nontumorigenic cell line (MCF-10A). The HNO donor also was more cytotoxic than the related NO donor. The basis for the observed specificity was investigated in terms of impact on metabolism, DNA damage and repair, apoptosis, angiogenesis and metastasis. The results suggest a significant pharmacological potential for treatment of breast cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Transdermal Delivery and Cutaneous Targeting of Antivirals using a Penetration Enhancer and Lysolipid Prodrugs

    Czech Academy of Sciences Publication Activity Database

    Diblíková, D.; Kopečná, M.; Školová, B.; Krečmerová, Marcela; Roh, J.; Hrabálek, A.; Vávrová, K.

    2014-01-01

    Roč. 31, č. 4 (2014), s. 1071-1081 ISSN 0724-8741 Grant - others:GA ČR(CZ) GAP207/11/0365 Institutional support: RVO:61388963 Keywords : acyclic nucleoside phosphonate antivirals * lysolipid prodrug * penetration enhancer * skin absorption * transdermal drug delivery Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 3.420, year: 2014

  19. Improved Synthesis of N-Benzylaminoferrocene-Based Prodrugs and Evaluation of Their Toxicity and Antileukemic Activity

    NARCIS (Netherlands)

    Daum, Steffen; Chekhun, Vasiliy F; Todor, Igor N; Lukianova, Natalia Yu; Shvets, Yulia V; Sellner, Leopold; Putzker, Kerstin; Lewis, Joe; Zenz, Thorsten; de Graaf, Inge A M; Groothuis, Geny M M; Casini, Angela; Zozulia, Oleksii; Hampel, Frank; Mokhir, Andriy

    2015-01-01

    We report on an improved method of synthesis of N-benzylaminoferrocene-based prodrugs and demonstrate its applicability by preparing nine new aminoferrocenes. Their effect on the viability of selected cancer cells having different p53 status was studied. The obtained data are in agreement with the

  20. Can primary reducing radicals be recruited for prodrug activation in tissue?

    International Nuclear Information System (INIS)

    Kriste, A.G.; Ferry, D.M.; Anderson, R.F.; Wilson, W.R.

    2003-01-01

    We have previously demonstrated that the nitroarylmethyl quaternary ammonium (NMQ) prodrugs of mechlorethamine (HN2) can be activated under anoxia by ionizing radiation (Kriste et al. Radiation Research, 158, 753 - 762, 2002). The HN2 released by these model compounds, however, is insufficiently potent for the prodrugs to be therapeutically useful. To address this concern, NMQ trigger units (4-nitroimidazole, 2-nitropyrrole and 3-nitrothiophene; all demonstrate one-electron release of HN2) were tethered to the DNA intercalator, AMAC (IC 50 values of 1.3 to 66 nM against human and rodent tumour cells). We now report whether AMAC can be radiolytically released from NMQ-AMAC prodrugs in a hypoxic tissue-like environment. Initially radiolysis was investigated in anoxic 0.1 M Formate buffer. Here, the G value for AMAC release was 0.33 ± 0.02μmol/J. In anoxic human plasma, radiolytic release was half as efficient (G(AMAC)= 0.18 ± 0.03μmol/J). To investigate AMAC release in tissue, V79-171b rodent tumour cells were seeded onto Millicell-CM cell culture inserts and grown to 10 - 20 cell diameters. These multicellular layers (MCLs) were equilibrated with prodrug (1μM, 4 hours), and transferred to a gassing chamber (95% nitrogen or oxygen, 2 minutes). MCLs were irradiated (high dose linear accelerator, 0 - 800 Gy, 35 Gy/pulse) and lysed. HPLC analysis indicated that each prodrug was taken up intracellularly to ca. 50 μM. Furthermore, AMAC release was linear with radiation dose and was inhibited under oxia. In this tissue, G values spanned a range from 9.0 to 15 nmol/J. These low values, ca. 5 % of the plasma value, are interpreted as reflecting unfavourable prodrug localization into acidic intracellular endosomes, with no clear E(1) dependance. Whether radiolytic reduction occurs via e aq - or H . abstraction to generate carbon-centred radicals is unknown. MCL studies with NMQ prodrugs that release alternate amine containing cytotoxins are currently in progress

  1. The impact of watershed management on coastal morphology: A case study using an integrated approach and numerical modeling

    Science.gov (United States)

    Samaras, Achilleas G.; Koutitas, Christopher G.

    2014-04-01

    Coastal morphology evolves as the combined result of both natural- and human- induced factors that cover a wide range of spatial and temporal scales of effect. Areas in the vicinity of natural stream mouths are of special interest, as the direct connection with the upstream watershed extends the search for drivers of morphological evolution from the coastal area to the inland as well. Although the impact of changes in watersheds on the coastal sediment budget is well established, references that study concurrently the two fields and the quantification of their connection are scarce. In the present work, the impact of land-use changes in a watershed on coastal erosion is studied for a selected site in North Greece. Applications are based on an integrated approach to quantify the impact of watershed management on coastal morphology through numerical modeling. The watershed model SWAT and a shoreline evolution model developed by the authors (PELNCON-M) are used, evaluating with the latter the performance of the three longshore sediment transport rate formulae included in the model formulation. Results document the impact of crop abandonment on coastal erosion (agricultural land decrease from 23.3% to 5.1% is accompanied by the retreat of ~ 35 m in the vicinity of the stream mouth) and show the effect of sediment transport formula selection on the evolution of coastal morphology. Analysis denotes the relative importance of the parameters involved in the dynamics of watershed-coast systems, and - through the detailed description of a case study - is deemed to provide useful insights for researchers and policy-makers involved in their study.

  2. On the hypothesis that quantum mechanism manifests classical mechanics: Numerical approach to the correspondence in search of quantum chaos

    International Nuclear Information System (INIS)

    Lee, Sang-Bong.

    1993-09-01

    Quantum manifestation of classical chaos has been one of the extensively studied subjects for more than a decade. Yet clear understanding of its nature still remains to be an open question partly due to the lack of a canonical definition of quantum chaos. The classical definition seems to be unsuitable in quantum mechanics partly because of the Heisenberg quantum uncertainty. In this regard, quantum chaos is somewhat misleading and needs to be clarified at the very fundamental level of physics. Since it is well known that quantum mechanics is more fundamental than classical mechanics, the quantum description of classically chaotic nature should be attainable in the limit of large quantum numbers. The focus of my research, therefore, lies on the correspondence principle for classically chaotic systems. The chaotic damped driven pendulum is mainly studied numerically using the split operator method that solves the time-dependent Schroedinger equation. For classically dissipative chaotic systems in which (multi)fractal strange attractors often emerge, several quantum dissipative mechanisms are also considered. For instance, Hoover's and Kubo-Fox-Keizer's approaches are studied with some computational analyses. But the notion of complex energy with non-Hermiticity is extensively applied. Moreover, the Wigner and Husimi distribution functions are examined with an equivalent classical distribution in phase-space, and dynamical properties of the wave packet in configuration and momentum spaces are also explored. The results indicate that quantum dynamics embraces classical dynamics although the classicalquantum correspondence fails to be observed in the classically chaotic regime. Even in the semi-classical limits, classically chaotic phenomena would eventually be suppressed by the quantum uncertainty

  3. Joining of polymer-metal lightweight structures using self-piercing riveting (SPR) technique: Numerical approach and simulation results

    Science.gov (United States)

    Amro, Elias; Kouadri-Henni, Afia

    2018-05-01

    Restrictions in pollutant emissions dictated at the European Commission level in the past few years have urged mass production car manufacturers to engage rapidly several strategies in order to reduce significantly the energy consumption of their vehicles. One of the most relevant taken action is light-weighting of body in white (BIW) structures, concretely visible with the increased introduction of polymer-based composite materials reinforced by carbon/glass fibers. However, the design and manufacturing of such "hybrid" structures is limiting the use of conventional assembly techniques like resistance spot welding (RSW) which are not transferable as they are for polymer-metal joining. This research aims at developing a joining technique that would eventually enable the assembly of a sheet molding compound (SMC) polyester thermoset-made component on a structure composed of several high strength steel grades. The state of the art of polymer-metal joining techniques highlighted the few ones potentially able to respond to the industrial challenge, which are: structural bonding, self-piercing riveting (SPR), direct laser joining and friction spot welding (FSpW). In this study, the promising SPR technique is investigated. Modelling of SPR process in the case of polymer-metal joining was performed through the building of a 2D axisymmetric FE model using the commercial code Abaqus CAE 6.10-1. Details of the numerical approach are presented with a particular attention to the composite sheet for which Mori-Tanaka's homogenization method is used in order to estimate overall mechanical properties. Large deformations induced by the riveting process are enabled with the use of a mixed finite element formulation ALE (arbitrary Lagrangian-Eulerian). FE model predictions are compared with experimental data followed by a discussion.

  4. A Numerical Study of Forbush Decreases with a 3D Cosmic-Ray Modulation Model Based on an SDE Approach

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Xi; Feng, Xueshang [SIGMA Weather Group, State Key Laboratory of Space Weather, National Space Science Center, Chinese Academy of Sciences, Beijing 100190 (China); Potgieter, Marius S. [Centre for Space Research, North-West University, Potchefstroom 2520 (South Africa); Zhang, Ming [Department of Physics and Space Sciences, Florida Institute of Technology, 150 West University Boulevard, Melbourne, FL 32901 (United States)

    2017-04-10

    Based on the reduced diffusion mechanism for producing Forbush decreases (Fds) in the heliosphere, we constructed a three-dimensional (3D) diffusion barrier, and by incorporating it into a stochastic differential equation (SDE) based time-dependent, cosmic-ray transport model, a 3D numerical model for simulating Fds is built and applied to a period of relatively quiet solar activity. This SDE model generally corroborates previous Fd simulations concerning the effects of the solar magnetic polarity, the tilt angle of the heliospheric current sheet (HCS), and cosmic-ray particle energy. Because the modulation processes in this 3D model are multi-directional, the barrier’s geometrical features affect the intensity profiles of Fds differently. We find that both the latitudinal and longitudinal extent of the barrier have relatively fewer effects on these profiles than its radial extent and the level of decreased diffusion inside the disturbance. We find, with the 3D approach, that the HCS rotational motion causes the relative location from the observation point to the HCS to vary, so that a periodic pattern appears in the cosmic-ray intensity at the observing location. Correspondingly, the magnitude and recovery time of an Fd change, and the recovering intensity profile contains oscillation as well. Investigating the Fd magnitude variation with heliocentric radial distance, we find that the magnitude decreases overall and, additionally, that the Fd magnitude exhibits an oscillating pattern as the radial distance increases, which coincides well with the wavy profile of the HCS under quiet solar modulation conditions.

  5. Flurbiprofen–antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling

    Directory of Open Access Journals (Sweden)

    Ashraf Z

    2016-07-01

    Full Text Available Zaman Ashraf,1,2 Alamgeer,3 Munazza Kanwal,1 Mubashir Hassan,2 Sahar Abdullah,3 Mamuna Waheed,3 Haseeb Ahsan,3 Song Ja Kim2 1Department of Chemistry, Allama Iqbal Open University, Islamabad, Pakistan; 2Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea; 3Department of Pharmacology, Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan Abstract: Flurbiprofen–antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (–COOH was temporarily masked by esterification with phenolic –OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, ­suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (P<0.001 reduced the inflammation against carrageenan and egg albumin-induced paw edema at 4 hours of study. The reduction in the size of the inflamed paw showed that most of the compounds inhibited the later phase of inflammation. The prodrug 2-oxo-2H-chromen-7-yl-2-(2-fluorobiphenyl-4-ylpropanoate (4b showed significant reduction in paw licking with percentage inhibition of 58%. It also exhibited higher analgesic activity, reducing the number of writhes with a percentage of 75%, whereas flurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer’s yeast-induced pyrexia model, and significant (P<0.001 reduction in rectal temperature was shown by all

  6. Synthesis, In Vitro and In Vivo Evaluation of the N-ethoxycarbonylmorpholine Ester of Diclofenac as a Prodrug

    OpenAIRE

    Jilani, Jamal; Idkaidek, Nasir; Alzoubi, Karem

    2014-01-01

    The N-ethoxycarbonylmorpholine moiety was evaluated as a novel prodrug moiety for carboxylic acid containing drugs represented by diclofenac (1). Compound 2, the N-ethoxycarbonylmorpholine ester of diclofenac was synthesized and evaluated as a potential prodrug. The stability of the synthesized prodrug was evaluated in solutions of pH 1 and 7.4, and in plasma. The ester’s half lives were found to be 8 h, 47 h and 21 min in pH 1, pH 7.4 and plasma, respectively. Equimolar doses of diclofenac...

  7. Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis

    DEFF Research Database (Denmark)

    Peiró Cadahía, Jorge; Bondebjerg, Jon; Hansen, Christian A.

    2018-01-01

    A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS...... assays. Selected candidates showed moderate to good solubility, high chemical and enzymatic stability, and therapeutic efficacy comparable to the parent drugs in the CIA model. Importantly, the prodrugs displayed the expected safer toxicity profile and increased therapeutic window compared to MTX and AMT...

  8. Comparative plasma disposition kinetics of albendazole and its new benzimidazol prodrug in dog.

    Science.gov (United States)

    Khalil, Z; El Karbane, M; Faouzi, M E A; Ansar, M; Azougagh, M; El Harti, J; Taoufik, J

    2016-01-01

    The comparative pharmacokinetic behavior of albendazole (ABZ) and its new benzimidazol prodrug [1-tert-butyloxycarbonyl-5-propylthio-1-H-benzimidazol-2ylcarbamate of methyl] (ABZBoc), following their oral administration (10mg/kg) to healthy dogs was explored. Blood samples were obtained serially over a 24h period after treatment, then the plasma was analyzed by high-performance liquid chromatography (HPLC) to search the albendazole metabolites (ABZSO and ABZSO2). However, the albendazole parent drug was not detectable at any time after both treatments (ABZ and ABZBoc). By albendazole metabolites (ABZSO and ABZSO2) were the analytes recovered in the plasma after oral administration of ABZ and ABZBoc. Furthermore, some amounts of ABZBoc were also available in the plasma samples treated with this new produg. The plasma profile of each analyte followed a similar pattern after both treatments, the active metabolite (ABZSO) was the major analyte recovered in plasma (between 1 and 24h post-treatment). The pharmacokinetic parameters of both groups were calculated (Cmax, Tmax, t1/2, AUC0-›∞), and analyzed using the Student's t-test, Palbendazole metabolites (ABZSO, ABZSO2) between the group treated with albendazole (group A) and that treated with ABZBoc prodrug (group B). Hence, the levels of the various pharmacokinetics parameters were low in the group treated with prodrug, as well they did not reach equivalent concentrations to that of albendazole. These differences between albendazole and its new prodrug may be explained by the fact that ABZBoc prodrug was not effectively reduced in the intestine of dogs. Copyright © 2015 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

  9. Sinking, merging and stationary plumes in a coupled chemotaxis-fluid model: a high-resolution numerical approach

    KAUST Repository

    Chertock, A.; Fellner, K.; Kurganov, A.; Lorz, A.; Markowich, P. A.

    2012-01-01

    examples, which illustrate (i) the formation of sinking plumes, (ii) the possible merging of neighbouring plumes and (iii) the convergence towards numerically stable stationary plumes. The examples with stable stationary plumes show how the surface

  10. An automated approach for solution based mesh adaptation to enhance numerical accuracy for a given number of grid cells

    NARCIS (Netherlands)

    Lucas, P.; Van Zuijlen, A.H.; Bijl, H.

    2009-01-01

    Mesh adaptation is a fairly established tool to obtain numerically accurate solutions for flow problems. Computational efficiency is, however, not always guaranteed for the adaptation strategies found in literature. Typically excessive mesh growth diminishes the potential efficiency gain. This

  11. Heat treatment of whole milk by the direct joule effect--experimental and numerical approaches to fouling mechanisms.

    Science.gov (United States)

    Fillaudeau, L; Winterton, P; Leuliet, J C; Tissier, J P; Maury, V; Semet, F; Debreyne, P; Berthou, M; Chopard, F

    2006-12-01

    The development of alternative technologies such as the direct Joule effect to pasteurize and sterilize food products is of great scientific and industrial interest. Our objective was 1) to gain insight into the ability to ensure ultra-high-temperature treatment of milk and 2) to investigate the links among thermal, hydraulic, and electrical phenomena in relation to fouling in a direct Joule effect heater. The ohmic heater [OH; E perpendicular to v (where E is the electrical field and v is the velocity); P (power) = 15 kW] was composed of 5 flat rectangular cells [e (space between the plate and electrode) = 15 mm, w (wall) = 76 mm, and L (length of the plate in plate heat exchanger or electrode) = 246 mm]--3 active cells to ensure heating and 2 (at the extremities) for electrical insulation and the recovery of leakage currents. In the first step, the thermal performance of the OH was investigated vs. the flow regimen [50 conductivity of fluids (0.1 thermal approach (thermal and electrical balance, modeling of the temperature profile of a fluid) and local analysis of the wall temperature of the electrode. An empirical correlation was established to estimate the temperature gradient, T(w)-T(b) (where T(w) is the wall temperature and T(b) is the product temperature) under clean conditions (without fouling) and was used to define operating conditions for pure-volume and direct-resistance heating. In the second step, the ability of OH to ensure the ultra-high-temperature treatment of whole milk was investigated and compared with a plate heat exchanger. Special care was taken to investigate the heat transfer phenomena occurring over a range of temperatures from 105 to 138 degrees C. This temperature range corresponds to the part of the process made critical by protein and mineral fouling. The objectives were 1) to demonstrate the ability of an OH to ensure heat treatment of milk, 2) to study the thermal and hydraulic performance with an increasing power and temperature

  12. A numerical approach for size optimization and performance prediction of solar P V-hybrid power systems

    International Nuclear Information System (INIS)

    Zahedi, A.; Calia, N.

    2001-10-01

    Iran is blessed with an abundance of sunlight almost all year round. so obviously, with the right planning and strategies that are coupled to the right technology and development in the market, the potential for the new renewable energies, specially solar photovoltaic, as an alternative source of power looks promising and is constantly gaining popularity. Development and application of new renewable energy in Iran, however, is still in its infancy and will require active support by government, utilities and financing institutions. some experts might argue that Iran has plenty of natural resources like oil and gas. We should not forget, however, that even in countries with cheap fossil energy, the P V system is an economical option in supplying electricity for remote located communities and facilities. But there are good reasons suggesting that like many other countries in the world, Iran also needs to be active in utilization of sun energy. The objectives of this paper are: to give a comprehensive overview on the current solar photovoltaic energy technology. (Authors of this paper believe that Photovoltaic is the most appropriate renewable energy technology for Iran); to present the results obtained from a study which has been carried out on the size optimization, cost calculation of the photovoltaic systems for climate conditions of Iran. The method presented in this paper can be used for systems of any size and application. A further objective of this paper is to present a numerical approach for evaluating the performance of P V-Hybrid power systems. A method is developed to predict the performance of all components integrated into a P V-hybrid system. The system under investigation is a hybrid power system, in which the integrated components are P V array, a battery bank for backing up the system and a diesel generator set for supporting the battery bank. State of charge of batteries is used as a measure for the performance of the system. The running time of

  13. Non linear shock wave propagation in heterogeneous fluids: a numerical approach beyond the parabolic approximation with application to sonic boom.

    Science.gov (United States)

    Dagrau, Franck; Coulouvrat, François; Marchiano, Régis; Héron, Nicolas

    2008-06-01

    Dassault Aviation as a civil aircraft manufacturer is studying the feasibility of a supersonic business jet with the target of an "acceptable" sonic boom at the ground level, and in particular in case of focusing. A sonic boom computational process has been performed, that takes into account meteorological effects and aircraft manoeuvres. Turn manoeuvres and aircraft acceleration create zones of convergence of rays (caustics) which are the place of sound amplification. Therefore two elements have to be evaluated: firstly the geometrical position of the caustics, and secondly the noise level in the neighbourhood of the caustics. The modelling of the sonic boom propagation is based essentially on the assumptions of geometrical acoustics. Ray tracing is obtained according to Fermat's principle as paths that minimise the propagation time between the source (the aircraft) and the receiver. Wave amplitude and time waveform result from the solution of the inviscid Burgers' equation written along each individual ray. The "age variable" measuring the cumulative nonlinear effects is linked to the ray tube area. Caustics are located as the place where the ray tube area vanishes. Since geometrical acoustics does not take into account diffraction effects, it breaks down in the neighbourhood of caustics where it would predict unphysical infinite pressure amplitude. The aim of this study is to describe an original method for computing the focused noise level. The approach involves three main steps that can be summarised as follows. The propagation equation is solved by a forward marching procedure split into three successive steps: linear propagation in a homogeneous medium, linear perturbation due to the weak heterogeneity of the medium, and non-linear effects. The first step is solved using an "exact" angular spectrum algorithm. Parabolic approximation is applied only for the weak perturbation due to the heterogeneities. Finally, non linear effects are performed by solving the

  14. Numerical Analysis of the Primary Breakup Applying the Embedded DNS Approach to a Generic Prefilming Airblast Atomizer

    Directory of Open Access Journals (Sweden)

    Benjamin Sauer

    2014-09-01

    Full Text Available An improved understanding of the breakup processes of two-phase flows is essential to effectively control the fuel atomization for future aircraft engines. A detailed insight into the phenomena of primary breakup is a major limitation in gaining this knowledge. Aircraft engines use airblast atomizers to provide the fuel atomization. The geometries of airblast atomizers are complex, the operating conditions are characterized by high Reynolds- and Weber numbers. Direct Numerical Simulations (DNS of liquid breakup under realistic conditions and geometries are hardly possible. The embedded DNS (eDNS concept aims to fill this gap. The concept consists of three steps: a geometry simplification, the generation of realistic boundary conditions for the DNS and the DNS of the breakup region. The realistic annular airblast atomizer geometry is simplified to a planar geometry. Inside this domain the eDNS is located. The eDNS domain requires the generation of boundary conditions. A zonal Large Eddy Simulation (LES of the turbulent channel flow is performed prior to the DNS. The parameters are stored transiently on the “virtual” DNS inlet planes. These variables are then mapped to the DNS. The Volume of fluid (VOF method is used to solve for the two-phase flow. DNS are performed for a shear-driven liquid wall film and for a generic planar prefilming airblast atomizer. As the Reynolds and Weber number for the first operating point (OP are low (Reair = 5,333/Wefilm = 1.9, the liquid wall film as well as the liquid sheet show no surface waves. For the second case with Reair = 13,333 and We film = 11.9, the surface appears more wrinkled and streamwise waves are transported along the wall for the shear-driven wall film. Instantaneous snapshots in 2–D and 3–D illustrate the qualitative behavior of the liquid sheet in time. Leaving the prefilmer trailing edge, the liquid sheet starts to oscillate in a sinusoidal fashion. This oscillation appears crucial for

  15. Lung cancer risk assessment due to traffic-generated particles exposure in urban street canyons: A numerical modelling approach.

    Science.gov (United States)

    Scungio, M; Stabile, L; Rizza, V; Pacitto, A; Russi, A; Buonanno, G

    2018-08-01

    Combustion-generated nanoparticles are responsible for negative health effects due to their ability to penetrate in the lungs, carrying toxic compounds with them. In urban areas, the coexistence of nanoparticle sources and particular street-building configurations can lead to very high particle exposure levels. In the present paper, an innovative approach for the evaluation of lung cancer incidence in street canyon due to exposure to traffic-generated particles was proposed. To this end, the literature-available values of particulate matter, PAHs and heavy metals emitted from different kind of vehicles were used to calculate the Excess Lifetime Cancer Risk (ELCR) at the tailpipe. The estimated ELCR was then used as input data in a numerical CFD (Computational Fluid Dynamics) model that solves the mass, momentum, turbulence and species transport equations, in order to evaluate the cancer risk in every point of interest inside the street canyon. Thus, the influence of wind speed and street canyon geometry (H/W, height of building, H and width of the street, W) on the ELCR at street level was evaluated by means of a CFD simulation. It was found that the ELCR calculated on the leeward and windward sides of the street canyon at a breathable height of 1.5 m, for people exposed 15 min per day for 20 years, is equal to 1.5 × 10 -5 and 4.8 × 10 -6 , respectively, for wind speed of 1 m/s and H/W equal to 1. The ELCR at street level results higher on the leeward side for aspect ratios equal to 1 and 3, while for aspect ratio equal to 2 it is higher on the windward side. In addition, the simulations showed that with the increasing of wind speed the ELCR becomes lower everywhere in the street canyon, due to the increased in dispersion. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

    Energy Technology Data Exchange (ETDEWEB)

    Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J. (CSIRO/MSE); (CSIRO/LW)

    2014-09-24

    We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

  17. Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA)

    Czech Academy of Sciences Publication Activity Database

    Majer, Pavel; Jančařík, Andrej; Krečmerová, Marcela; Tichý, Tomáš; Tenora, Lukáš; Wozniak, K.; Wu, Y.; Pommier, E.; Ferraris, D.; Rais, R.; Slusher, B. S.

    2016-01-01

    Roč. 59, č. 6 (2016), s. 2810-2819 ISSN 0022-2623 Institutional support: RVO:61388963 Keywords : glutamate carboxypeptidase II * glutamate * 2-PMPA * prodrug Subject RIV: CC - Organic Chemistry Impact factor: 6.259, year: 2016

  18. Dinitrobenzamide mustard prodrugs - hypoxic cytotoxins and dual substrates for E.coli nitroreductase

    International Nuclear Information System (INIS)

    Patterson, A.V.; Hogg, A.; Pullen, S.; Degenkolbe, A.; Li, D.; Chappell, A.; Ying, S.; Atwell, G.J.; Denny, W.A.; Anderson, R.F.; Wilson, W.R.

    2003-01-01

    Conditional replicating adenoviral vectors (CRAds) have received considerable attention as therapeutic tools in combination with radiotherapy. Viral distribution and micro-regional geometry are likely to be important issues in the treatment of human solid tumours with gene therapy, particularly following intravenous virus administration. The use of CRAds that are 'armed' with enzyme/prodrug systems may overcome some of the perceived limitations; CRAds can redistribute and self-amplify in a cytolytic fashion whilst prodrug metabolites may elicit a local bystander effect. Either or both of these cytotoxic properties could have favourable interactions with radiotherapy (IR). Nevertheless, they may be insufficient to avoid pockets of vector-naive tumour cells beyond the diffusion limits of cytotoxic prodrug metabolites, such as when perivascular seeding occurs. Under such circumstances hypoxic tumour cells may represent the least accessible compartment for vector transfection; the same tumour subpopulation that is likely to be radioresistant. E.coli nitroreductase (NTR) can bioactivate dinitrobenzamide mustards (DNBMs) and is a promising enzyme/prodrug system for 'arming' CRAds. Notably DNMBs can also be activated by endogenous human reductases under low oxygen conditions providing an opportunity to identify dual hypoxic cytotoxins/NTR substrates that may circumvent some of the geometry issues and provide complementarity with IR. To identify a prodrug for NTR that is also active as a hypoxic cytotoxin in vivo. From a set of 164 DNB prodrugs, 19 with favourable activity in vitro against a panel of four NTR-expressing cancer cells were selected and screened for activity as hypoxic cytotoxins in vitro. Measured E17 values ranged from -444 to -366 mV. Seven DNBMs possessed acceptable hypoxic selectivity against the human NSCLC cell line A549WT or clones engineered to overexpress either a human single-electron reductase, cytochrome P450 reductase (A549P450R), or oxic

  19. Bending of Euler-Bernoulli nanobeams based on the strain-driven and stress-driven nonlocal integral models: a numerical approach

    Science.gov (United States)

    Oskouie, M. Faraji; Ansari, R.; Rouhi, H.

    2018-04-01

    Eringen's nonlocal elasticity theory is extensively employed for the analysis of nanostructures because it is able to capture nanoscale effects. Previous studies have revealed that using the differential form of the strain-driven version of this theory leads to paradoxical results in some cases, such as bending analysis of cantilevers, and recourse must be made to the integral version. In this article, a novel numerical approach is developed for the bending analysis of Euler-Bernoulli nanobeams in the context of strain- and stress-driven integral nonlocal models. This numerical approach is proposed for the direct solution to bypass the difficulties related to converting the integral governing equation into a differential equation. First, the governing equation is derived based on both strain-driven and stress-driven nonlocal models by means of the minimum total potential energy. Also, in each case, the governing equation is obtained in both strong and weak forms. To solve numerically the derived equations, matrix differential and integral operators are constructed based upon the finite difference technique and trapezoidal integration rule. It is shown that the proposed numerical approach can be efficiently applied to the strain-driven nonlocal model with the aim of resolving the mentioned paradoxes. Also, it is able to solve the problem based on the strain-driven model without inconsistencies of the application of this model that are reported in the literature.

  20. A numerical-statistical approach to determining the representative elementary volume (REV of cement paste for measuring diffusivity

    Directory of Open Access Journals (Sweden)

    Zhang, M. Z.

    2010-12-01

    Full Text Available Concrete diffusivity is a function of its microstructure on many scales, ranging from nanometres to millimetres. Multi-scale techniques are therefore needed to model this parameter. Representative elementary volume (REV, in conjunction with the homogenization principle, is one of the most common multi-scale approaches. This study aimed to establish a procedure for establishing the REV required to determine cement paste diffusivity based on a three-step, numerical-statistical approach. First, several series of 3D cement paste microstructures were generated with HYMOSTRUC3D, a cement hydration and microstructure model, for different volumes of cement paste and w/c ratios ranging from 0.30 to 0.60. Second, the finite element method was used to simulate the diffusion of tritiated water through these microstructures. Effective cement paste diffusivity values for different REVs were obtained by applying Fick’s law. Finally, statistical analysis was used to find the fluctuation in effective diffusivity with cement paste volume, from which the REV was then determined. The conclusion drawn was that the REV for measuring diffusivity in cement paste is 100x100x100 μm3.

    La difusividad del hormigón depende de su microestructura a numerosas escalas, desde nanómetros hasta milímetros, por lo que se precisa de técnicas multiescala para representar este parámetro. Junto con el principio de homogeneización, uno de los métodos multiescala más habituales es el volumen elemental representativo (VER. El objeto de este estudio era establecer un procedimiento que permitiera determinar el VER necesario para calcular la difusividad de la pasta de cemento, basándose en un método numéricoestadístico que consta de tres etapas. Primero, se crearon varias series de microestructuras de pasta de cemento en 3D con HYMOSTRUC3D, un programa que permite crear un modelo de la hidratación y microestructura del cemento. Luego se empleó el método de

  1. Synthesis of mutual azo prodrugs of anti-inflammatory agents and peptides facilitated by α-aminoisobutyric acid.

    Science.gov (United States)

    Kennedy, David A; Vembu, Nagarajan; Fronczek, Frank R; Devocelle, Marc

    2011-12-02

    Reported is the synthesis of azo mutual prodrugs of the nonsteroidal anti-inflammatory agents (NSAIDs) 4-aminophenylacetic acid (4-APAA) or 5-aminosalicylic acid (5-ASA) with peptides, including an antibiotic peptide temporin analogue modified at the amino terminal by an α-aminoisobutyric acid (Aib) residue. These prodrugs are designed for colonic delivery of two agents to treat infection and inflammation by the bacterial pathogen Clostridium difficile . © 2011 American Chemical Society

  2. A Validation Approach for Quasistatic Numerical/Experimental Indentation Analysis in Soft Materials Using 3D Digital Image Correlation.

    Science.gov (United States)

    Felipe-Sesé, Luis; López-Alba, Elías; Hannemann, Benedikt; Schmeer, Sebastian; Diaz, Francisco A

    2017-06-28

    A quasistatic indentation numerical analysis in a round section specimen made of soft material has been performed and validated with a full field experimental technique, i.e., Digital Image Correlation 3D. The contact experiment specifically consisted of loading a 25 mm diameter rubber cylinder of up to a 5 mm indentation and then unloading. Experimental strains fields measured at the surface of the specimen during the experiment were compared with those obtained by performing two numerical analyses employing two different hyperplastic material models. The comparison was performed using an Image Decomposition new methodology that makes a direct comparison of full-field data independently of their scale or orientation possible. Numerical results show a good level of agreement with those measured during the experiments. However, since image decomposition allows for the differences to be quantified, it was observed that one of the adopted material models reproduces lower differences compared to experimental results.

  3. Prodrugs of purine and pyrimidine analogues for the intestinal di/tri-peptide transporter PepT1

    DEFF Research Database (Denmark)

    Thomsen, Anne Engelbrecht; Friedrichsen, Gerda Marie; Sørensen, Arne Hagsten

    2003-01-01

    , novel L-Glu-Sar and D-Glu-Ala ester prodrugs of acyclovir and 1-(2-hydroxyethyl)-linked thymine were synthesized and their affinities for hPepT1 in Caco-2 cells were determined. Furthermore, the degradation of the prodrugs was investigated in various aqueous and biological media and compared...... to the corresponding hydrolysis of the prodrug valaciclovir. Affinity studies showed that the L-Glu-Sar prodrugs had high affinity for hPepT1 (K(i) approximately 0.2-0.3 mM), whereas the D-Glu-Ala prodrugs had poor affinity (K(i) approximately 50 mM). The pH-rate profiles of the prodrugs D-Glu[1-(2-hydroxyethyl......)thymine]-Ala and L-Glu[acyclovir]-Sar showed specific base catalyzed degradation at pH above 4.5 and 5.5, respectively. This implicates that the degradation rates at pH approximately 7.4 (t(1/2) approximately 3.5 and 5.5 h) are approximately 25 times faster than at upper small intestinal pH approximately 6.0. In 10...

  4. Redox-responsive core cross-linked prodrug micelles prepared by click chemistry for pH-triggered doxorubicin delivery

    Directory of Open Access Journals (Sweden)

    X. T. Cao

    2017-10-01

    Full Text Available A pH-triggered drug delivery system of degradable core cross-linked (CCL prodrug micelles was prepared by click chemistry. Doxorubicin conjugated block copolymers of azido functional poly(ethylene oxide-b-poly(glycidyl methacrylate were synthesized by the combination of RAFT polymerization, epoxide ring-opening reaction, and acid-cleavable hydrazone linkages. The CCL prodrug micelles were produced by the reaction of dipropargyl 3,3′-dithiodipropionate and dipropargyl adipate cross-linking agents with the azido groups of the micellar core via alkyne-azide click reaction, which were denoted as CCL/SS and CCL/noSS, respectively. The TEM images of CCL/SS prodrug micelles showed a spherical shape with the average diameter of 61.0 nm from water, and the shape was maintained with an increased diameter upon dilution with 5-fold DMF. The high DOX conjugation efficiency was 88.4%. In contrast to a very slow DOX release from CCL/SS prodrug micelles under the physiological condition (pH 7.4, the drug release is much faster (90% at pH 5.0 and 10 mM of GSH after 96 h. The cytotoxicity test and confocal laser scanning microscopy analysis revealed that CCL/SS prodrug micelles had much enhanced intracellular drug release capability in HepG2 cells than CCL/noSS prodrug micelles.

  5. Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation.

    Science.gov (United States)

    Chayrov, Radoslav L; Stylos, Evgenios K; Chatziathanasiadou, Maria V; Chuchkov, Kiril N; Tencheva, Aleksandra I; Kostagianni, Androniki D; Milkova, Tsenka S; Angelova, Assia L; Galabov, Angel S; Shishkov, Stoyan A; Todorov, Daniel G; Tzakos, Andreas G; Stankova, Ivanka G

    2018-05-19

    Bile acid prodrugs have served as a viable strategy for refining the pharmaceutical profile of parent drugs through utilizing bile acid transporters. A series of three ester prodrugs of the antiherpetic drug acyclovir (ACV) with the bile acids cholic, chenodeoxycholic and deoxycholic were synthesized and evaluated along with valacyclovir for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The in vitro antiviral activity of the three bile acid prodrugs was also evaluated against Epstein-Barr virus (EBV). Plasma stability assays, utilizing ultra-high performance liquid chromatography coupled with tandem mass spectrometry, in vitro cytotoxicity and inhibitory experiments were conducted in order to establish the biological profile of ACV prodrugs. The antiviral assays demonstrated that ACV-cholate had slightly better antiviral activity than ACV against HSV-1, while it presented an eight-fold higher activity with respect to ACV against HSV-2. ACV-chenodeoxycholate presented a six-fold higher antiviral activity against HSV-2 with respect to ACV. Concerning EBV, the highest antiviral effect was demonstrated by ACV-chenodeoxycholate. Human plasma stability assays revealed that ACV-deoxycholate was more stable than the other two prodrugs. These results suggest that decorating the core structure of ACV with bile acids could deliver prodrugs with amplified antiviral activity.

  6. An efficient approach to numerical study of the coupled-BBM system with B-spline collocation method

    Directory of Open Access Journals (Sweden)

    khalid ali

    2016-11-01

    Full Text Available In the present paper, a numerical method is proposed for the numerical solution of a coupled-BBM system with appropriate initial and boundary conditions by using collocation method with cubic trigonometric B-spline on the uniform mesh points. The method is shown to be unconditionally stable using von-Neumann technique. To test accuracy the error norms2L, ?L are computed. Furthermore, interaction of two and three solitary waves are used to discuss the effect of the behavior of the solitary waves after the interaction. These results show that the technique introduced here is easy to apply. We make linearization for the nonlinear term.

  7. Water Curtain System Pre-design for Crude Oil Storage URCs : A Numerical Modeling and Genetic Programming Approach

    NARCIS (Netherlands)

    Ghotbi Ravandi, Ebrahim; Rahmannejad, Reza; Karimi-Nasab, Saeed; Sarrafi, Amir; Raoof, Amir

    In this paper the main criteria of the water curtain system for unlined rock caverns (URCs) is described. By the application of numerical modeling and genetic programming (GP), a method for water curtain system pre-design for Iranian crude oil storage URCs (common dimension worldwide) is presented.

  8. Numerical Simulation of Complex Multi-Fluid Flows using a Combined Immersed Boundary and Volume of Fluid Approach

    NARCIS (Netherlands)

    Deen, N.G.; van Sint Annaland, M.; Kuipers, J.A.M.

    2007-01-01

    In this paper a simulation model is presented for the Direct Numerical Simulation (DNS) of complex multi-fluid flows in which simultaneously (moving) deformable (drops or bubbles) and non-deformable (moving) elements (particles) are present, possibly with the additional presence of free surfaces.

  9. A Space-Time Finite Element Approach to the Numerical Simulation of Vascular Fluid-Solid Interaction

    NARCIS (Netherlands)

    Vlijm, E.J.; Van Brummelen, E.H.

    2008-01-01

    Numerical studies of cardiovascular diseases like arteriosclerosis have gained increasing attention the last decade. The modeling of blood, blood vessel and their coupling, shows to be a challenging problem. In this thesis a two-dimensional model has been constructed and its behaviour has been

  10. Acyclovir prodrug for the intestinal di/tri-peptide transporter PEPT1

    DEFF Research Database (Denmark)

    Thomsen, Anne Engelbrecht; Christensen, Michael Søberg; Bagger, Morten Aavad

    2004-01-01

    It has previously been shown that the prodrug Glu(acyclovir)-Sar has a high affinity for PEPT1 in Caco-2 cells. However, affinity does not necessarily lead to translocation by the transporter which is necessary for achieving an increased oral bioavailability. Therefore i.v. and p.o. doses of Glu......(acyclovir)-Sar, acyclovir and valacyclovir were given to rats and the collected blood samples were analysed via LC-MS-MS. Furthermore, Caco-2 cell monolayers were exposed apically to Glu(acyclovir)-Sar, acyclovir, and valacyclovir and the concentration of drug and prodrugs in the cell extracts were determined and taken...... as a measure for intracellular accumulation. In addition, bi-directional transport studies of Glu(acyclovir)-Sar across Caco-2 cell monolayers and in vitro metabolism studies of Glu(acyclovir)-Sar in various media of rat origin were performed. For these purposes HPLC-UV analysis was applied. Oral...

  11. Pharmacokinetics of penciclovir after oral administration of its prodrug famciclovir to horses.

    Science.gov (United States)

    Tsujimura, Koji; Yamada, Masayuki; Nagata, Shun-ichi; Yamanaka, Takashi; Nemoto, Manabu; Kondo, Takashi; Kurosawa, Masahiko; Matsumura, Tomio

    2010-03-01

    We investigated the pharmacokinetics of penciclovir after oral administration of its prodrug famciclovir to horses. Following an oral dose of famciclovir at 20 mg/kg, maximum plasma concentrations of penciclovir occurred between 0.75 and 1.5 hr (mean 0.94 + or - 0.38 hr) after dosing and were in the range 2.22 to 3.56 microg/ml (mean 2.87 + or - 0.61 microg/ml). The concentrations of penciclovir declined in a biphasic manner after the peak concentration was attained. The mean half-life of the rapid elimination phase was 1.73 + or - 0.34 hr whereas that of the slow elimination phase was 34.34 + or - 13.93 hr. These pharmacokinetic profiles observed were similar to those of another antiherpesvirus drug, acyclovir, previously reported in horses following oral dosing of its prodrug valacyclovir.

  12. Strategy for Imidazotetrazine Prodrugs with Anticancer Activity Independent of MGMT and MMR

    Science.gov (United States)

    2012-01-01

    The imidazotetrazine ring is an acid-stable precursor and prodrug of highly reactive alkyl diazonium ions. We have shown that this reactivity can be managed productively in an aqueous system for the generation of aziridinium ions with 96% efficiency. The new compounds are potent DNA alkylators and have antitumor activity independent of the O6-methylguanine-DNA methyltransferase and DNA mismatch repair constraints that limit the use of Temozolomide. PMID:24900418

  13. Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers.

    Science.gov (United States)

    Dahan, Arik; Wolk, Omri; Yang, Peihua; Mittal, Sachin; Wu, Zhiqian; Landowski, Christopher P; Amidon, Gordon L

    2014-12-01

    The efficacy of chemotherapeutic drugs is often offset by severe side effects attributable to poor selectivity and toxicity to normal cells. Recently, the enzyme dipeptidyl peptidase IV (DPPIV) was considered as a potential target for the delivery of chemotherapeutic drugs. The purpose of this study was to investigate the feasibility of targeting chemotherapeutic drugs to DPPIV as a strategy to enhance their specificity. The expression profile of DPPIV was obtained for seven cancer cell lines using DNA microarray data from the DTP database, and was validated by RT-PCR. A prodrug was then synthesized by linking the cytotoxic drug melphalan to a proline-glycine dipeptide moiety, followed by hydrolysis studies in the seven cell lines with a standard substrate, as well as the glycyl-prolyl-melphalan (GP-Mel). Lastly, cell proliferation studies were carried out to demonstrate enzyme-dependent activation of the candidate prodrug. The relative RT-PCR expression levels of DPPIV in the cancer cell lines exhibited linear correlation with U95Av2 Affymetrix data (r(2) = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r(2) = 0.96). The significantly higher antiproliferative activity of GP-Mel in Caco-2 cells (GI₅₀ = 261 μM) compared to that in SK-MEL-5 cells (GI₅₀ = 807 μM) was consistent with the 9-fold higher specific activity of the prodrug in Caco-2 cells (5.14 pmol/min/μg protein) compared to SK-MEL-5 cells (0.68 pmol/min/μg protein) and with DPPIV expression levels in these cells. Our results demonstrate the great potential to exploit DPPIV as a prodrug activating enzyme for efficient chemotherapeutic drug targeting.

  14. Sinking, merging and stationary plumes in a coupled chemotaxis-fluid model: a high-resolution numerical approach

    KAUST Repository

    Chertock, A.

    2012-02-02

    Aquatic bacteria like Bacillus subtilis are heavier than water yet they are able to swim up an oxygen gradient and concentrate in a layer below the water surface, which will undergo Rayleigh-Taylor-type instabilities for sufficiently high concentrations. In the literature, a simplified chemotaxis-fluid system has been proposed as a model for bio-convection in modestly diluted cell suspensions. It couples a convective chemotaxis system for the oxygen-consuming and oxytactic bacteria with the incompressible Navier-Stokes equations subject to a gravitational force proportional to the relative surplus of the cell density compared to the water density. In this paper, we derive a high-resolution vorticity-based hybrid finite-volume finite-difference scheme, which allows us to investigate the nonlinear dynamics of a two-dimensional chemotaxis-fluid system with boundary conditions matching an experiment of Hillesdon et al. (Bull. Math. Biol., vol. 57, 1995, pp. 299-344). We present selected numerical examples, which illustrate (i) the formation of sinking plumes, (ii) the possible merging of neighbouring plumes and (iii) the convergence towards numerically stable stationary plumes. The examples with stable stationary plumes show how the surface-directed oxytaxis continuously feeds cells into a high-concentration layer near the surface, from where the fluid flow (recurring upwards in the space between the plumes) transports the cells into the plumes, where then gravity makes the cells sink and constitutes the driving force in maintaining the fluid convection and, thus, in shaping the plumes into (numerically) stable stationary states. Our numerical method is fully capable of solving the coupled chemotaxis-fluid system and enabling a full exploration of its dynamics, which cannot be done in a linearised framework. © 2012 Cambridge University Press.

  15. Construction and cellular uptake behavior of redox-sensitive docetaxel prodrug-loaded liposomes.

    Science.gov (United States)

    Ren, Guolian; Jiang, Mengjuan; Guo, Weiling; Sun, Bingjun; Lian, He; Wang, Yongjun; He, Zhonggui

    2018-01-01

    A redox-responsive docetaxel (DTX) prodrug consisting of a disulfide linkage between DTX and vitamin E (DTX-SS-VE) was synthesized in our laboratory and was successfully formulated into liposomes. The aim of this study was to optimize the formulation and investigate the cellular uptake of DTX prodrug-loaded liposomes (DPLs). The content of DTX-SS-VE was determined by ultrahigh-performance liquid chromatography (UPLC). The formulation and process were optimized using entrapment efficiency (EE), drug-loading (DL), particle size and polydispersity index (PDI) as the evaluation indices. The optimal formulation was as follows: drug/lipid ratio of 1:12, cholesterol/lipid ratio of 1:10, hydration temperature of 40 °C, sonication power and time of 400 W and 5 min. The EE, DL and particle size of the optimized DPLs were 97.60 ± 0.03%, 7.09 ± 0.22% and 93.06 ± 0.72 nm, respectively. DPLs had good dilution stability under the physiological conditions over 24 h. In addition, DPLs were found to enter tumor cells via different pathways and released DTX from the prodrug to induce apoptosis. Taken together, the optimized formulation and process were found to be a simple, stable and applicable method for the preparation of DPLs that could successfully escape from lysosomes.

  16. Photo-triggered fluorescent theranostic prodrugs as DNA alkylating agents for mechlorethamine release and spatiotemporal monitoring.

    Science.gov (United States)

    Cao, Yanting; Pan, Rong; Xuan, Weimin; Wei, Yongyi; Liu, Kejian; Zhou, Jiahong; Wang, Wei

    2015-06-28

    We describe a new theranostic strategy for selective delivery and spatiotemporal monitoring of mechlorethamine, a DNA alkylating agent. A photo-responsive prodrug is designed and composed of a photolabile o-nitrophenylethyl group, a DNA alkylating mechlorethamine drug and a coumarin fluorophore. Masking of the "N" in mechlorethamine in a positively charged state in the prodrug renders it inactive, non-toxic, selective and non-fluorescent. Indeed, the stable prodrug shows negligible cytotoxicity towards normal cells with and without UV activation and is completely non-fluorescent. However, upon photo-irradiation, the active mechlorethamine is released and induces efficient DNA cross-links, accompanied by a strong fluorescence enhancement (152 fold). Furthermore, DNA cross-linking activity from the release can be transformed into anticancer activity observed in in vitro studies of tumor cells. Importantly, the drug release progress and the movement can be conveniently monitored by fluorescence spectroscopy. The mechanistic study proves that the DNA cross-linking activity is mainly due to the release of DNA alkylating mechlorethamine. Altogether, the studies show the power of the theranostic strategy for efficient therapy in cancer treatment.

  17. Direct chemical grafted curcumin on halloysite nanotubes as dual-responsive prodrug for pharmacological applications.

    Science.gov (United States)

    Massaro, M; Amorati, R; Cavallaro, G; Guernelli, S; Lazzara, G; Milioto, S; Noto, R; Poma, P; Riela, S

    2016-04-01

    Covalently functionalized halloysite nanotubes (HNTs) were successfully employed as dual-responsive nanocarriers for curcumin (Cur). Particularly, we synthesized HNT-Cur prodrug with a controlled curcumin release on dependence of both intracellular glutathione (GSH) and pH conditions. In order to obtain HNT-Cur produgs, halloysite was firstly functionalized with cysteamine through disulphide linkage. Afterwards, curcumin molecules were chemically conjugated to the amino end groups of halloysite via Schiff's base formation. The successful functionalization of halloysite was proved by thermogravimetric analysis, FT-IR spectroscopy, dynamic light scattering and scanning electron microscopy. Experimental data confirmed the presence of curcumin on HNT external surface. Moreover, we investigated the kinetics of curcumin release by UV-vis spectroscopy, which highlighted that HNT-Cur prodrug possesses dual stimuli-responsive ability upon exposure to GSH-rich or acidic environment. In vitro antiproliferative and antioxidant properties of HNT-Cur prodrug were studied with the aim to explore their potential applications in pharmaceutics. This work puts forward an efficient strategy to prepare halloysite based nanocarriers with controlled drug delivery capacity through direct chemical grafting with stimuli-responsive linkage. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Synthesis and biological evaluation of novel 10-substituted-7-ethyl-10-hydroxycamptothecin (SN-38) prodrugs.

    Science.gov (United States)

    Zhou, Mo; Liu, Meixia; He, Xinhua; Yu, Hong; Wu, Di; Yao, Yishan; Fan, Shiyong; Zhang, Ping; Shi, Weiguo; Zhong, Bohua

    2014-11-27

    In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo.

  19. Synthesis and Biological Evaluation of Novel 10-Substituted-7-ethyl-10-hydroxycamptothecin (SN-38 Prodrugs

    Directory of Open Access Journals (Sweden)

    Mo Zhou

    2014-11-01

    Full Text Available In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2, novel prodrugs of SN-38 (3 were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11 in a human colon xenograft model in vivo.

  20. In Vitro and In Vivo Evaluation of Microparticulate Drug Delivery Systems Composed of Macromolecular Prodrugs

    Directory of Open Access Journals (Sweden)

    Yoshiharu Machida

    2008-08-01

    Full Text Available Macromolecular prodrugs are very useful systems for achieving controlled drug release and drug targeting. In particular, various macromolecule-antitumor drug conjugates enhance the effectiveness and improve the toxic side effects. Also, polymeric micro- and nanoparticles have been actively examined and their in vivo behaviors elucidated, and it has been realized that their particle characteristics are very useful to control drug behavior. Recently, researches based on the combination of the concepts of macromolecular prodrugs and micro- or nanoparticles have been reported, although they are limited. Macromolecular prodrugs enable drugs to be released at a certain controlled release rate based on the features of the macromolecule-drug linkage. Micro- and nanoparticles can control in vivo behavior based on their size, surface charge and surface structure. These merits are expected for systems produced by the combination of each concept. In this review, several micro- or nanoparticles composed of macromolecule-drug conjugates are described for their preparation, in vitro properties and/or in vivo behavior.

  1. The antiproliferative cytostatic effects of a self-activating viridin prodrug

    Science.gov (United States)

    Smith, Adam; Blois, Joseph; Yuan, Hushan; Aikawa, Elena; Ellson, Christian; Figueiredo, Jose-Luiz; Weissleder, Ralph; Kohler, Rainer; Yaffe, Michael B.; Cantley, Lewis C.; Josephson, Lee

    2009-01-01

    Although viridins like wortmannin (Wm) have long been examined as anticancer agents, their ability to self-activate has only recently been recognized. Here, we describe the cytostatic effects of a self-activating viridin (SAV), which is an inactive, polymeric prodrug. SAV self-activates to generate a bioactive, fluorescent viridin NBD-Wm with a half-time of 9.2 hours. With cultured A549 cells, 10 µmol/L SAV caused growth arrest without inducing apoptosis or cell death, a cytostatic action markedly different from other chemotherapeutic agents (vinblastine, camptothecin, and paclitaxel). In vivo, a SAV dosing of 1 mg/kg once in 48 hours (i.p.) resulted in growth arrest of an A549 tumor xenograft, with growth resuming when dosing ceased. With a peak serum concentration of SAV of 2.36 µmol/L (at 2 hours post i.p. injection), the concentration of bioactive NBD-Wm was 41 nmol/L based on the partial inhibition of neutrophil respiratory burst. Therefore, SAV was present as an inactive prodrug in serum (peak = 2.36 µmol/L), which generated low concentrations of active viridin (41 nmol/L). SAV is a prodrug, the slowrelease and cytostatic activities of which suggest that it might be useful as a component of metronomic-based chemotherapeutic strategies. PMID:19509266

  2. Improved synthesis of N-benzylaminoferrocene-based prodrugs and evaluation of their toxicity and antileukemic activity.

    Science.gov (United States)

    Daum, Steffen; Chekhun, Vasiliy F; Todor, Igor N; Lukianova, Natalia Yu; Shvets, Yulia V; Sellner, Leopold; Putzker, Kerstin; Lewis, Joe; Zenz, Thorsten; de Graaf, Inge A M; Groothuis, Geny M M; Casini, Angela; Zozulia, Oleksii; Hampel, Frank; Mokhir, Andriy

    2015-02-26

    We report on an improved method of synthesis of N-benzylaminoferrocene-based prodrugs and demonstrate its applicability by preparing nine new aminoferrocenes. Their effect on the viability of selected cancer cells having different p53 status was studied. The obtained data are in agreement with the hypothesis that the toxicity of aminoferrocenes is not dependent upon p53 status. Subsequently the toxicity of a selected prodrug (4) was investigated ex vivo using rat precision cut liver slices and in vivo on hybrid male mice BDF1. In both experiments no toxicity was observed: ex vivo, up to 10 μM; in vivo, up to 6 mg/kg. Finally, prodrug 4 was shown to extend the survival of BDF1 mice carrying L1210 leukemia from 13.7 ± 0.6 days to 17.5 ± 0.7 days when injected daily 6 times at a dose of 26 μg/kg starting from the second day after injection of L1210 cells.

  3. A unique highly hydrophobic anticancer prodrug self-assembled nanomedicine for cancer therapy.

    Science.gov (United States)

    Ren, Guolian; Jiang, Mengjuan; Xue, Peng; Wang, Jing; Wang, Yongjun; Chen, Bo; He, Zhonggui

    2016-11-01

    In contrast with common thought, we generated highly hydrophobic anticancer prodrug self-assembled nanoparticles without the aid of surface active substances, based on the conjugation of docetaxel to d-α-tocopherol succinate. The reduction-sensitive prodrug was synthesized with a disulfide bond inserted into the linker and was compared with a control reduction-insensitive prodrug. The morphology and stability of self-assembled nanoparticles were investigated. Cytotoxicity and apoptosis assays showed that the reduction-sensitive nanoparticles had higher anticancer activity than the reduction-insensitive nanoparticles. The reduction-sensitive nanoparticles exhibited favorable in vivo antitumor activity and tolerance compared with docetaxel Tween80-containing formulation and the reduction-insensitive nanoparticles. Taken together, the unique nanomedicine demonstrated a number of advantages: (i) ease and reproducibility of preparation, (ii) high drug payload, (iii) superior stability, (iv) prolonged circulation, and (v) improved therapeutic effect. This highly reproducible molecular assembly strategy should motivate the development of new nanomedicines. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Experimental determination of surface heat transfer coefficient in a dry ice-ethanol cooling bath using a numerical approach.

    Science.gov (United States)

    Santos, M V; Sansinena, M; Zaritzky, N; Chirife, J

    BACKGROUND: Dry ice-ethanol bath (-78 degree C) have been widely used in low temperature biological research to attain rapid cooling of samples below freezing temperature. The prediction of cooling rates of biological samples immersed in dry ice-ethanol bath is of practical interest in cryopreservation. The cooling rate can be obtained using mathematical models representing the heat conduction equation in transient state. Additionally, at the solid cryogenic-fluid interface, the knowledge of the surface heat transfer coefficient (h) is necessary for the convective boundary condition in order to correctly establish the mathematical problem. The study was to apply numerical modeling to obtain the surface heat transfer coefficient of a dry ice-ethanol bath. A numerical finite element solution of heat conduction equation was used to obtain surface heat transfer coefficients from measured temperatures at the center of polytetrafluoroethylene and polymethylmetacrylate cylinders immersed in a dry ice-ethanol cooling bath. The numerical model considered the temperature dependence of thermophysical properties of plastic materials used. A negative linear relationship is observed between cylinder diameter and heat transfer coefficient in the liquid bath, the calculated h values were 308, 135 and 62.5 W/(m 2 K) for PMMA 1.3, PTFE 2.59 and 3.14 cm in diameter, respectively. The calculated heat transfer coefficients were consistent among several replicates; h in dry ice-ethanol showed an inverse relationship with cylinder diameter.

  5. Novel L-Dopa and dopamine prodrugs containing a 2-phenyl-imidazopyridine moiety.

    Science.gov (United States)

    Denora, Nunzio; Laquintana, Valentino; Lopedota, Angela; Serra, Mariangela; Dazzi, Laura; Biggio, Giovanni; Pal, Dhananjay; Mitra, Ashim K; Latrofa, Andrea; Trapani, Giuseppe; Liso, Gaetano

    2007-07-01

    The aim of this study was to gain insight into the feasibility of enhancing the delivery of L-Dopa and dopamine to the brain by linking these neurotransmitters and L-Dopa ethyl ester to 2-phenyl-3-carboxymethyl-imidazopyridine compounds giving rise to the so-called Dopimid compounds. A number of Dopimid compounds were synthesized and both stability and binding studies to dopaminergic and benzodiazepine receptors were performed. To evaluate whether Dopimid compounds are P-gp substrates, [(3)H]ritonavir uptake experiments and bi-directional transport studies on confluent MDCKII-MDR1 monolayers were carried out. The brain penetration properties of Dopimid compounds were estimated by the Clark's computational model and evaluated by investigation of their transport across BBMECs monolayers. The dopamine levels following the intraperitoneal administration of the selected Dopimid compounds were measured in vivo by using brain microdialysis in rat. Tested compounds were adequately stable in solution buffered at pH 7.4 but undergo faster cleavage in dilute rat serum at 37 degrees C. Receptor binding studies showed that Dopimid compounds are essentially devoid of affinity for dopaminergic and benzodiazepine receptors. [(3)H]ritonavir uptake experiments indicated that selected Dopimid compounds, like L-Dopa and dopamine hydrochloride, are not substrates of P-gp and it was also confirmed by bi-directional transport experiments across MDCKII-MDR1 monolayers. By Clark's model a significant brain penetration was deduced for L-Dopa ethyl ester and dopamine derivatives. Transport studies involving BBMECs monolayers indicated that some of these compounds should be able to cross the BBB. Interestingly, the rank order of apparent permeability (P (app)) values observed in these assays parallels that calculated by the computational approach. Brain microdialysis experiments in rat showed that intraperitoneal acute administration of some Dopimid compounds induced a dose-dependent increase

  6. Numerical modeling of the thermomechanical behavior of networks of underground galleries for the storage of the radioactive waste: approach by homogenization

    International Nuclear Information System (INIS)

    Zokimila, P.

    2005-10-01

    Deep geological disposal is one of the privileged options for the storage of High Level radioactive waste. A good knowledge of the behavior and properties of the potential geological formations as well as theirs evolution in time under the effect of the stress change induced by a possible installation of storage is required. The geological formation host will be subjected to mechanical and thermal solicitations due respectively to the excavation of the disposal tunnels and the release of heat of the canisters of radioactive waste. These thermomechanical solicitations will generate a stress relief in the host layer and disposal tunnels deformations as well as the extension of the damaged zones (EDZ) could cause local and global instabilities. This work aims to develop calculation methods to optimize numerical modeling of the thermoelastic behavior of the disposal at a large scale and to evaluate thermomechanical disturbance induced by storage on the geological formation host. Accordingly, after a presentation of the state of knowledge on the thermomechanical aspects of the rocks related to deep storage, of numerical modeling 2D and 3D of the thermoelastic behavior of individual disposal tunnel and a network of tunnels were carried out by a discrete approach. However, this classical approach is penalizing to study the global behavior of disposal storage. To mitigate that, an approach of numerical modeling, based on homogenization of periodic structures, was proposed. Formulations as numerical procedures were worked out to calculate the effective thermoelastic behavior of an equivalent heterogeneous structure. The model, obtained by this method, was validated with existing methods of homogenization such as the self-consistent model, as well as the Hashin-Shtrikman bounds. The comparison between the effective thermoelastic behavior and current thermoelastic behavior of reference showed a good coherence of the results. For an application to deep geological storage, the

  7. Anticancer activities of emetine prodrugs that are proteolytically activated by the prostate specific antigen (PSA) and evaluation of in vivo toxicity of emetine derivatives.

    Science.gov (United States)

    Akinboye, Emmanuel S; Rosen, Marc D; Bakare, Oladapo; Denmeade, Samuel R

    2017-12-15

    Emetine is a small molecule protein synthesis inhibitor that is toxic to all cell types and therefore suitable for complete killing of all types of heterogeneous cancer cells within a tumor. It becomes significantly inactive (non-toxic) when derivatized at its N-2' secondary amine. This provides a strategy for targeting emetine to cancerous tumor without killing normal cells. In this report, PSA activatable peptide prodrugs of emetine were synthesized. To overcome steric hindrances and enhance protease specific cleavage, a 2-stage prodrug activation process was needed to release emetine in cancer cells. In this 2-stage process, emetine prodrug intermediates are coupled to PSA peptide substrate (Ac-His-Ser-Ser-Lys-Leu-Gln) to obtain the full prodrug. Both prodrug intermediates 10 (Ala-Pro-PABC-Emetine) and 14 (Ser-Leu-PABC-Emetine) were evaluated for kinetics of hydrolysis to emetine and potency [Where PABC = p-aminobenzyloxycarbonyl]. While both intermediates quantitatively liberate emetine when incubated under appropriate conditions, upon coupling of PSA substrate to give the full prodrugs, only prodrug 16, the prodrug obtained from 14 was hydrolyzable by PSA. Cytotoxicity studies in PSA producing LNCaP and CWR22Rv1 confirm the activation of the prodrug by PSA with an IC 50 of 75 nM and 59 nM respectively. The cytotoxicity of 16 is significantly reduced in cell lines that do not produce PSA. Further, in vivo toxicity studies are done on these prodrugs and other derivatives of emetine. The results show the significance of conformational modulation in obtaining safe emetine prodrugs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Platinum(iv) prodrug conjugated Pd@Au nanoplates for chemotherapy and photothermal therapy

    Science.gov (United States)

    Shi, Saige; Chen, Xiaolan; Wei, Jingping; Huang, Yizhuan; Weng, Jian; Zheng, Nanfeng

    2016-03-01

    Owing to the excellent near infrared (NIR) light absorption and efficient passive targeting toward tumor tissue, two-dimensional (2D) core-shell PEGylated Pd@Au nanoplates have great potential in both photothermal therapy and drug delivery systems. In this work, we successfully conjugate Pd@Au nanoplates with a platinum(iv) prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)2] to obtain a nanocomposite (Pd@Au-PEG-Pt) for combined photothermal-chemotherapy. The prepared Pd@Au-PEG-Pt nanocomposite showed excellent stability in physiological solutions and efficient Pt(iv) prodrug loading. Once injected into biological tissue, the Pt(iv) prodrug was easily reduced by physiological reductants (e.g. ascorbic acid or glutathione) into its cytotoxic and hydrophilic Pt(ii) form and released from the original nanocomposite, and the NIR laser irradiation could accelerate the release of Pt(ii) species. More importantly, Pd@Au-PEG-Pt has high tumor accumulation (29%ID per g), which makes excellent therapeutic efficiency at relatively low power density possible. The in vivo results suggested that, compared with single therapy the combined thermo-chemotherapy treatment with Pd@Au-PEG-Pt resulted in complete destruction of the tumor tissue without recurrence, while chemotherapy using Pd@Au-PEG-Pt without irradiation or photothermal treatment using Pd@Au-PEG alone did not. Our work highlights the prospects of a feasible drug delivery strategy of the Pt prodrug by using 2D Pd@Au nanoplates as drug delivery carriers for multimode cancer treatment.Owing to the excellent near infrared (NIR) light absorption and efficient passive targeting toward tumor tissue, two-dimensional (2D) core-shell PEGylated Pd@Au nanoplates have great potential in both photothermal therapy and drug delivery systems. In this work, we successfully conjugate Pd@Au nanoplates with a platinum(iv) prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)2] to obtain a nanocomposite (Pd@Au-PEG-Pt) for combined photothermal-chemotherapy. The

  9. Probabilistic approach of resource assessment in Kerinci geothermal field using numerical simulation coupling with monte carlo simulation

    Science.gov (United States)

    Hidayat, Iki; Sutopo; Pratama, Heru Berian

    2017-12-01

    The Kerinci geothermal field is one phase liquid reservoir system in the Kerinci District, western part of Jambi Province. In this field, there are geothermal prospects that identified by the heat source up flow inside a National Park area. Kerinci field was planned to develop 1×55 MWe by Pertamina Geothermal Energy. To define reservoir characterization, the numerical simulation of Kerinci field is developed by using TOUGH2 software with information from conceptual model. The pressure and temperature profile well data of KRC-B1 are validated with simulation data to reach natural state condition. The result of the validation is suitable matching. Based on natural state simulation, the resource assessment of Kerinci geothermal field is estimated by using Monte Carlo simulation with the result P10-P50-P90 are 49.4 MW, 64.3 MW and 82.4 MW respectively. This paper is the first study of resource assessment that has been estimated successfully in Kerinci Geothermal Field using numerical simulation coupling with Monte carlo simulation.

  10. A Novel Hybrid Approach for Numerical Modeling of the Nucleating Flow in Laval Nozzle and Transonic Steam Turbine Blades

    Directory of Open Access Journals (Sweden)

    Edris Yousefi Rad

    2017-08-01

    Full Text Available In the present research, considering the importance of desirable steam turbine design, improvement of numerical modeling of steam two-phase flows in convergent and divergent channels and the blades of transonic steam turbines has been targeted. The first novelty of this research is the innovative use of combined Convective Upstream Pressure Splitting (CUSP and scalar methods to update the flow properties at each calculation point. In other words, each property (density, temperature, pressure and velocity at each calculation point can be computed from either the CUSP or scalar method, depending on the least deviation criterion. For this reason this innovative method is named “hybrid method”. The next novelty of this research is the use of an inverse method alongside the proposed hybrid method to find the amount of the important parameter z in the CUSP method, which is herein referred to as “CUSP’s convergence parameter”. Using a relatively simple computational grid, firstly, five cases with similar conditions to those of the main cases under study in this research with available experimental data were used to obtain the value of z by the Levenberg-Marquardt inverse method. With this innovation, first, an optimum value of z = 2.667 was obtained using the inverse method and then directly used for the main cases considered in the research. Given that the aim is to investigate the two-dimensional, steady state, inviscid and adiabatic modeling of steam nucleating flows in three different nozzle and turbine blade geometries, flow simulation was performed using a relatively simple mesh and the innovative proposed hybrid method (scalar + CUSP, with the desired value of z = 2.667 . A comparison between the results of the hybrid modeling of the three main cases with experimental data showed a very good agreement, even within shock zones, including the condensation shock region, revealing the efficiency of this numerical modeling method innovation

  11. Finite-time and finite-size scalings in the evaluation of large-deviation functions: Numerical approach in continuous time.

    Science.gov (United States)

    Guevara Hidalgo, Esteban; Nemoto, Takahiro; Lecomte, Vivien

    2017-06-01

    Rare trajectories of stochastic systems are important to understand because of their potential impact. However, their properties are by definition difficult to sample directly. Population dynamics provides a numerical tool allowing their study, by means of simulating a large number of copies of the system, which are subjected to selection rules that favor the rare trajectories of interest. Such algorithms are plagued by finite simulation time and finite population size, effects that can render their use delicate. In this paper, we present a numerical approach which uses the finite-time and finite-size scalings of estimators of the large deviation functions associated to the distribution of rare trajectories. The method we propose allows one to extract the infinite-time and infinite-size limit of these estimators, which-as shown on the contact process-provides a significant improvement of the large deviation function estimators compared to the standard one.

  12. Finite-time and finite-size scalings in the evaluation of large-deviation functions: Numerical approach in continuous time

    Science.gov (United States)

    Guevara Hidalgo, Esteban; Nemoto, Takahiro; Lecomte, Vivien

    2017-06-01

    Rare trajectories of stochastic systems are important to understand because of their potential impact. However, their properties are by definition difficult to sample directly. Population dynamics provides a numerical tool allowing their study, by means of simulating a large number of copies of the system, which are subjected to selection rules that favor the rare trajectories of interest. Such algorithms are plagued by finite simulation time and finite population size, effects that can render their use delicate. In this paper, we present a numerical approach which uses the finite-time and finite-size scalings of estimators of the large deviation functions associated to the distribution of rare trajectories. The method we propose allows one to extract the infinite-time and infinite-size limit of these estimators, which—as shown on the contact process—provides a significant improvement of the large deviation function estimators compared to the standard one.

  13. Design, Synthesis and Biological Evaluation of Brain-Targeted Thiamine Disulfide Prodrugs of Ampakine Compound LCX001

    Directory of Open Access Journals (Sweden)

    Dian Xiao

    2016-04-01

    Full Text Available Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of “lock-in” can be used to solve these problems. A series of thiamine disulfide prodrugs 7a–7f of ampakine compound LCX001 was synthesized and evaluated. The trials in vitro showed that prodrugs 7e, 7d, 7f possessed a certain stability in plasma and quickly decomposed in brain homogenate by the disulfide reductase. In vivo, prodrug 7e decreased the peripheral distribution of LCX001 and significantly increased brain distribution of LCX001 after i.v. administration. This compound showed 2.23- and 3.29-fold greater increases in the AUC0-t and MRT0-t of LCX001 in brain, respectively, than did LCX001 itself. A preliminary pharmacodynamic study indicated that the required molar dose of prodrug 7e was only one eighth that of LCX001 required to achieve the same effect in mice. These findings provide an important reference to evaluate the clinical outlook of ampakine compounds.

  14. Enhanced Absorption and Growth Inhibition with Amino Acid Monoester Prodrugs of Floxuridine by Targeting hPEPT1 Transporters

    Directory of Open Access Journals (Sweden)

    Gordon L. Amidon

    2008-06-01

    Full Text Available A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5′-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50 ranging from 0.7 – 2.3 mM in Caco-2 and 2.0 – 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 – 5.31 x 10-6 cm/sec and floxuridine (0.48 x 10-6 cm/sec were much higher than that of 5-FU (0.038 x 10-6 cm/sec. MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1 exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy.

  15. Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters.

    Science.gov (United States)

    Tsume, Yasuhiro; Vig, Balvinder S; Sun, Jing; Landowski, Christopher P; Hilfinger, John M; Ramachandran, Chandrasekharan; Amidon, Gordon L

    2008-06-28

    A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5'-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50) ranging from 0.7 - 2.3 mM in Caco-2 and 2.0 - 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 - 5.31 x 10(-6 )cm/sec) and floxuridine (0.48 x 10(-6 )cm/sec) were much higher than that of 5-FU (0.038 x 10(-6) cm/sec). MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1) exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy.

  16. An Equation-Type Approach for the Numerical Solution of the Partial Differential Equations Governing Transport Phenomena in Porous Media

    KAUST Repository

    Sun, Shuyu; Salama, Amgad; El-Amin, Mohamed

    2012-01-01

    A new technique for the numerical solution of the partial differential equations governing transport phenomena in porous media is introduced. In this technique, the governing equations as depicted from the physics of the problem are used without extra manipulations. In other words, there is no need to reduce the number of governing equations by some sort of mathematical manipulations. This technique enables the separation of the physics part of the problem and the solver part, which makes coding more robust and could be used in several other applications with little or no modifications (e.g., multi-phase flow in porous media). In this method, one abandons the need to construct the coefficient matrix for the pressure equation. Alternatively, the coefficients are automatically generated within the solver routine. We show examples of using this technique to solving several flow problems in porous media.

  17. Numerical Multilevel Upscaling for Incompressible Flow in Reservoir Simulation: An Element-based Algebraic Multigrid (AMGe) Approach

    DEFF Research Database (Denmark)

    Christensen, Max la Cour; Villa, Umberto; Engsig-Karup, Allan Peter

    2017-01-01

    associated with non-planar interfaces between agglomerates, the coarse velocity space has guaranteed approximation properties. The employed AMGe technique provides coarse spaces with desirable local mass conservation and stability properties analogous to the original pair of Raviart-Thomas and piecewise......We study the application of a finite element numerical upscaling technique to the incompressible two-phase porous media total velocity formulation. Specifically, an element agglomeration based Algebraic Multigrid (AMGe) technique with improved approximation proper ties [37] is used, for the first...... discontinuous polynomial spaces, resulting in strong mass conservation for the upscaled systems. Due to the guaranteed approximation properties and the generic nature of the AMGe method, recursive multilevel upscaling is automatically obtained. Furthermore, this technique works for both structured...

  18. Fourth-order numerical solutions of diffusion equation by using SOR method with Crank-Nicolson approach

    Science.gov (United States)

    Muhiddin, F. A.; Sulaiman, J.

    2017-09-01

    The aim of this paper is to investigate the effectiveness of the Successive Over-Relaxation (SOR) iterative method by using the fourth-order Crank-Nicolson (CN) discretization scheme to derive a five-point Crank-Nicolson approximation equation in order to solve diffusion equation. From this approximation equation, clearly, it can be shown that corresponding system of five-point approximation equations can be generated and then solved iteratively. In order to access the performance results of the proposed iterative method with the fourth-order CN scheme, another point iterative method which is Gauss-Seidel (GS), also presented as a reference method. Finally the numerical results obtained from the use of the fourth-order CN discretization scheme, it can be pointed out that the SOR iterative method is superior in terms of number of iterations, execution time, and maximum absolute error.

  19. An Equation-Type Approach for the Numerical Solution of the Partial Differential Equations Governing Transport Phenomena in Porous Media

    KAUST Repository

    Sun, Shuyu

    2012-06-02

    A new technique for the numerical solution of the partial differential equations governing transport phenomena in porous media is introduced. In this technique, the governing equations as depicted from the physics of the problem are used without extra manipulations. In other words, there is no need to reduce the number of governing equations by some sort of mathematical manipulations. This technique enables the separation of the physics part of the problem and the solver part, which makes coding more robust and could be used in several other applications with little or no modifications (e.g., multi-phase flow in porous media). In this method, one abandons the need to construct the coefficient matrix for the pressure equation. Alternatively, the coefficients are automatically generated within the solver routine. We show examples of using this technique to solving several flow problems in porous media.

  20. On the instability of a 3-dimensional attachment line boundary layer: Weakly nonlinear theory and a numerical approach

    Science.gov (United States)

    Hall, P.; Malik, M. R.

    1984-01-01

    The instability of a three dimensional attachment line boundary layer is considered in the nonlinear regime. Using weakly nonlinear theory, it is found that, apart from a small interval near the (linear) critical Reynolds number, finite amplitude solutions bifurcate subcritically from the upper branch of the neutral curve. The time dependent Navier-Stokes equations for the attachment line flow have been solved using a Fourier-Chebyshev spectral method and the subcritical instability is found at wavenumbers that correspond to the upper branch. Both the theory and the numerical calculations show the existence of supercritical finite amplitude (equilibrium) states near the lower branch which explains why the observed flow exhibits a preference for the lower branch modes. The effect of blowing and suction on nonlinear stability of the attachment line boundary layer is also investigated.

  1. On the instability of a three-dimensional attachment-line boundary layer - Weakly nonlinear theory and a numerical approach

    Science.gov (United States)

    Hall, P.; Malik, M. R.

    1986-01-01

    The instability of a three-dimensional attachment-line boundary layer is considered in the nonlinear regime. Using weakly nonlinear theory, it is found that, apart from a small interval near the (linear) critical Reynolds number, finite-amplitude solutions bifurcate subcritically from the upper branch of the neutral curve. The time-dependent Navier-Stokes equations for the attachment-line flow have been solved using a Fourier-Chebyshev spectral method and the subcritical instability is found at wavenumbers that correspond to the upper branch. Both the theory and the numerical calculations show the existence of supercritical finite-amplitude (equilibrium) states near the lower branch which explains why the observed flow exhibits a preference for the lower branch modes. The effect of blowing and suction on nonlinear stability of the attachment-line boundary layer is also investigated.

  2. Investigation of dynamics of discrete framed structures by a numerical wave-based method and an analytical homogenization approach

    Directory of Open Access Journals (Sweden)

    Changwei Zhou

    2017-02-01

    Full Text Available In this article, the analytical homogenization method of periodic discrete media (HPDM and the numerical condensed wave finite element method (CWFEM are employed to study the longitudinal and transverse vibrations of framed structures. The valid frequency range of the HPDM is re-evaluated using the wave propagation feature identified by the CWFEM. The relative error of the wavenumber by the HPDM compared to that by the CWFEM is illustrated in functions of frequency and scale ratio. A parametric study on the thickness of the structure is carried out where the dispersion relation and the relative error are given for three different thicknesses. The dynamics of a finite structure such as natural frequency and forced response are also investigated using the HPDM and the CWFEM.

  3. Complex transfers in porous media: some physical and numerical approaches; Transferts complexes en milieux poreux: quelques approches physiques et numeriques

    Energy Technology Data Exchange (ETDEWEB)

    Maugis, P

    2006-06-15

    The feasibility and safety of nuclear waste storage containers is studied. The thermodynamics of water/air flow is described and applied, via a simplified numerical model, to a simple experimental apparatus yielding heat pipe effect. The 2D influence of deterministic boundary conditions is important on kinematics and transport. Dispersivity depends on the nonuniform flow type and integrates the often marginal Gaussian part of plume spreading. A new algorithm, based on jump locality and recalibration, avoids the small bias induced by inter-cell diffusive jumps. Several algorithms modeling transport of decaying, soluble, sorbing, or precipitating species are compared. Stability and precision criteria are analyzed. Up-stream over-precipitation and negative down-stream concentrations are observed for high solubility contrasts. (author)

  4. A combined experimental and numerical approach for the control and monitoring of the SPES target during operation at high temperature

    Energy Technology Data Exchange (ETDEWEB)

    Ballan, Michele [National Institute of Nuclear Physics – Legnaro National Laboratories (INFN-LNL), Viale dell’Università 2, Legnaro, 35020 Padova (Italy); Department of Physics and Earth Sciences, University of Ferrara, via Saragat 1, 44122 Ferrara (Italy); Manzolaro, Mattia [National Institute of Nuclear Physics – Legnaro National Laboratories (INFN-LNL), Viale dell’Università 2, Legnaro, 35020 Padova (Italy); Department of Industrial Engineering (DII), University of Padova, via Venezia 1, 35131 Padova (Italy); Meneghetti, Giovanni [Department of Industrial Engineering (DII), University of Padova, via Venezia 1, 35131 Padova (Italy); Andrighetto, Alberto [National Institute of Nuclear Physics – Legnaro National Laboratories (INFN-LNL), Viale dell’Università 2, Legnaro, 35020 Padova (Italy); Monetti, Alberto [National Institute of Nuclear Physics – Legnaro National Laboratories (INFN-LNL), Viale dell’Università 2, Legnaro, 35020 Padova (Italy); Department of Industrial Engineering (DII), University of Padova, via Venezia 1, 35131 Padova (Italy); Bisoffi, Giovanni; Prete, Gianfranco [National Institute of Nuclear Physics – Legnaro National Laboratories (INFN-LNL), Viale dell’Università 2, Legnaro, 35020 Padova (Italy)

    2016-06-01

    The SPES project at INFN-LNL aims at the production of neutron-rich Radioactive Ion Beams (RIBs) using the ISOL (Isotope Separation On Line) technique. A 40 MeV 200 μA proton beam will directly impinge a uranium carbide target, generating approximately 10{sup 13} fissions per second. The target system is installed under vacuum inside a water-cooled chamber, and have to maintain high working temperatures, close to 2000 °C. During operation the proton beam provides the heating power required to keep the target at the desired temperature level. As a consequence, its characteristics have to be strictly controlled in order to avoid undesired overheating. According to the original design of the control system, the proton beam can be suddenly interrupted in case of out of range vacuum or cooling water flow levels. With the aim to improve the reliability of the control system a set of temperature sensors has been installed close to the target. Their types and installation positions were defined taking into consideration the detailed information coming from a dedicated thermal–electric model that allowed to investigate the most critical and inaccessible target hot-spots. This work is focused on the definition and experimental validation of the aforementioned numerical model. Its results were used to appropriately install two type C thermocouples, a PT100 thermo-resistance and a residual primary beam current detector. In addition the numerical model will be used for the definition of appropriate thresholds for each installed temperature sensor, since it allows to define a relationship between the locally measured values with the overall calculated temperature field. In case of over temperatures the monitoring system will send warning signals or in case interrupt the proton beam.

  5. A combined experimental and numerical approach for the control and monitoring of the SPES target during operation at high temperature

    Science.gov (United States)

    Ballan, Michele; Manzolaro, Mattia; Meneghetti, Giovanni; Andrighetto, Alberto; Monetti, Alberto; Bisoffi, Giovanni; Prete, Gianfranco

    2016-06-01

    The SPES project at INFN-LNL aims at the production of neutron-rich Radioactive Ion Beams (RIBs) using the ISOL (Isotope Separation On Line) technique. A 40 MeV 200 μA proton beam will directly impinge a uranium carbide target, generating approximately 1013 fissions per second. The target system is installed under vacuum inside a water-cooled chamber, and have to maintain high working temperatures, close to 2000 °C. During operation the proton beam provides the heating power required to keep the target at the desired temperature level. As a consequence, its characteristics have to be strictly controlled in order to avoid undesired overheating. According to the original design of the control system, the proton beam can be suddenly interrupted in case of out of range vacuum or cooling water flow levels. With the aim to improve the reliability of the control system a set of temperature sensors has been installed close to the target. Their types and installation positions were defined taking into consideration the detailed information coming from a dedicated thermal-electric model that allowed to investigate the most critical and inaccessible target hot-spots. This work is focused on the definition and experimental validation of the aforementioned numerical model. Its results were used to appropriately install two type C thermocouples, a PT100 thermo-resistance and a residual primary beam current detector. In addition the numerical model will be used for the definition of appropriate thresholds for each installed temperature sensor, since it allows to define a relationship between the locally measured values with the overall calculated temperature field. In case of over temperatures the monitoring system will send warning signals or in case interrupt the proton beam.

  6. Relationship between electrical conductivity anisotropy and fabric anisotropy in granular materials during drained triaxial compressive tests: a numerical approach

    Science.gov (United States)

    Niu, Qifei; Revil, André; Li, Zhaofeng; Wang, Yu-Hsing

    2017-07-01

    The anisotropy of granular media and its evolution during shearing are important aspects required in developing physics-based constitutive models in Earth sciences. The development of relationships between geoelectrical properties and the deformation of porous media has applications to the monitoring of faulting and landslides. However, such relationships are still poorly understood. In this study, we first investigate the definition of the electrical conductivity anisotropy tensor of granular materials in presence of surface conductivity of the grains. Fabric anisotropy is related to the components of the fabric tensor. We define an electrical anisotropy factor based on the Archie's exponent second-order symmetric tensor m of granular materials. We use numerical simulations to confirm a relationship between the evolution of electrical and fabric anisotropy factors during shearing. To realize the simulations, we build a virtual laboratory in which we can easily perform synthetic experiments. We first simulate drained compressive triaxial tests of loose and dense granular materials (porosity 0.45 and 0.38, respectively) using the discrete element method. Then, the electrical conductivity tensor of a set of deformed synthetic samples is computed using the finite-difference method. The numerical results show that shear strains are responsible for a measurable anisotropy in the bulk conductivity of granular media. The observed electrical anisotropy response, during shearing, is distinct for dense and loose synthetic samples. Electrical and fabric anisotropy factors exhibit however a unique linear correlation, regardless of the shear strain and the initial state (porosity) of the synthetic samples. The practical implication of this finding confirms the usefulness of the electrical conductivity method in studying the fabric tensor of granular media. This result opens the door in using time-lapse electrical resistivity to study non-intrusively the evolution of anisotropy

  7. Polymer-gel remediation of CO2 migration through faults and numerical simulations addressing feasibility of novel approaches

    NARCIS (Netherlands)

    Pizzocolo, F.; Hewson, C.W.; Heege, J.H. ter

    2016-01-01

    Subsurface CO2 storage has been identified as one of the key methods to reduce the emission of CO2 to the atmosphere. Remediation or mitigation of unwanted migration from potential storage sites requires novel approaches for which feasibility is yet to be demonstrated. This study focuses on a

  8. Ocular Pharmacokinetics of Acyclovir Amino Acid Ester Prodrugs in the Anterior Chamber: Evaluation of Their Utility in Treating Ocular HSV Infections

    Science.gov (United States)

    Katragadda, Suresh; Gunda, Sriram; Hariharan, Sudharshan; Mitra, Ashim K.

    2008-01-01

    Purpose To evaluate in vivo corneal absorption of the amino acid prodrugs of acyclovir (ACV) using a topical well model and microdialysis in rabbits. Methods Stability of L-Alanine-ACV (AACV), L-Serine-ACV (SACV), L-Isoleucine-ACV (IACV), γ-Glutamate-ACV (EACV) and L-Valine-ACV (VACV) prodrugs was evaluated in various ocular tissues. Dose dependent toxicity of these prodrugs was also examined in rabbit primary corneal epithelial cell culture (rPCEC) using 96-well based cell proliferation assay. In vivo ocular bioavailability of these compounds was also evaluated with a combination of topical well infusion and aqueous humor microdialysis techniques. Results Among the amino acid ester prodrugs, SACV was most stable in aqueous humor. Enzymatic degradation of EACV was the least compared to all other prodrugs. Cellular toxicity of all the prodrugs was significantly less compared to trifluorothymidine (TFT) at 5mM. Absorption rate constants of all the compounds were found to be lower than the elimination rate constants. All the prodrugs showed similar terminal elimination rate constants (λz). SACV and VACV exhibited approximately two fold increase in area under the curve (AUC) relative to ACV (p cornea at varying rates (ka) thereby leading to varying extents (AUC). The amino acid ester prodrug, SACV owing to its enhanced stability, comparable AUC, and high concentration at last time point (Clast) seems to be a promising candidate for the treatment of ocular HSV infections. PMID:18472234

  9. Numerical investigation of a joint approach to thermal energy storage and compressed air energy storage in aquifers

    International Nuclear Information System (INIS)

    Guo, Chaobin; Zhang, Keni; Pan, Lehua; Cai, Zuansi; Li, Cai; Li, Yi

    2017-01-01

    Highlights: •One wellbore-reservoir numerical model was built to study the impact of ATES on CAESA. •With high injection temperature, the joint of ATES can improve CAESA performance. •The considerable utilization of geothermal occurs only at the beginning of operations. •Combination of CAESA and ATES can be achieved in common aquifers. -- Abstract: Different from conventional compressed air energy storage (CAES) systems, the advanced adiabatic compressed air energy storage (AA-CAES) system can store the compression heat which can be used to reheat air during the electricity generation stage. Thus, AA-CAES system can achieve a higher energy storage efficiency. Similar to the AA-CAES system, a compressed air energy storage in aquifers (CAESA) system, which is integrated with an aquifer thermal energy storage (ATES) could possibly achieve the same objective. In order to investigate the impact of ATES on the performance of CAESA, different injection air temperature schemes are designed and analyzed by using numerical simulations. Key parameters relative to energy recovery efficiencies of the different injection schemes, such as pressure distribution and temperature variation within the aquifers as well as energy flow rate in the injection well, are also investigated in this study. The simulations show that, although different injection schemes have a similar overall energy recovery efficiency (∼97%) as well as a thermal energy recovery efficiency (∼79.2%), the higher injection air temperature has a higher energy storage capability. Our results show the total energy storage for the injection air temperature at 80 °C is about 10% greater than the base model scheme at 40 °C. Sensitivity analysis reveal that permeability of the reservoir boundary could have significant impact on the system performance. However, other hydrodynamic and thermodynamic properties, such as the storage reservoir permeability, thermal conductivity, rock grain specific heat and rock

  10. Study of the band-gap structure of a 1D-photonic crystal by using different numerical approaches

    International Nuclear Information System (INIS)

    Chen, Jian-Bo; Chen, Yue-Rui; Shen, Yan; Zhou, Wei-Xi; Ren, Jiu-Chun; Zheng, Yu-Xiang; Chen, Liang-Yao

    2010-01-01

    Comparative studies between the transfer matrices method (TMM) and plane wave method (PWM) approaches have been performed on 1D photonics crystal under different conditions to show the differences between these two kinds of calculations. TMM is suitable for the design of 1D photonic crystal device with high precision and is in good agreement with experimental results, but is not suitable for the 2D and 3D photonic structures which are limited by the complicated boundary conditions at micro interfaces. The result based on the PWM approach to deal approximately with the photonic structure in approximation has not yet been strictly verified by experiment, not even for 1D photonic crystal structures. More efforts will be required to explore its validation under all physical conditions to enhance its application.

  11. A numerical approach to the simulation of one-phase and two phase reactor coolant flow around nuclear fuel spacers

    International Nuclear Information System (INIS)

    Stosic, Z.V.; Stevanovic, V.D.

    2001-01-01

    A methodology for the simulation and analysis of one-phase and two-phase coolant flows around one or a row of spacers is presented. It is based on the multidimensional two-fluid mass, momentum and energy balance equations and application of adequate turbulence models. Necessary closure laws for interfacial transfer processes are presented. The stated general approach enables simulation and analyses of reactor coolant flow around spacers on different scale levels of the rod bundle geometry: detailed modelling of coolant flow around spacers and investigation of the influence of spacer's geometry on the coolant thermal-hydraulics, as well as prediction of global thermal-hydraulic parameters within the whole rod bundle with the investigation of the influence of rows of spacers on the bulk thermal-hydraulic processes. Sample problems are included illustrating these different modelling approaches. (author)

  12. A Smart Europium-Ruthenium Complex as Anticancer Prodrug: Controllable Drug Release and Real-Time Monitoring under Different Light Excitations.

    Science.gov (United States)

    Li, Hongguang; Xie, Chen; Lan, Rongfeng; Zha, Shuai; Chan, Chi-Fai; Wong, Wing-Yan; Ho, Ka-Lok; Chan, Brandon Dow; Luo, Yuxia; Zhang, Jing-Xiang; Law, Ga-Lai; Tai, William C S; Bünzli, Jean-Claude G; Wong, Ka-Leung

    2017-11-09

    A unique, dual-function, photoactivatable anticancer prodrug, RuEuL, has been tailored that features a ruthenium(II) complex linked to a cyclen-europium chelate via a π-conjugated bridge. Under irradiation at 488 nm, the dark-inactive prodrug undergoes photodissociation, releasing the DNA-damaging ruthenium species. Under evaluation-window irradiation (λ irr = one-photon 350 nm or two-photon 700 nm), the drug delivery process can be quantitatively monitored in real-time because of the long-lived red europium emission. Linear relationships between released drug concentration and ESI-MS or luminescence responses are established. Finally, the efficiency of the new prodrug is demonstrated both in vitro RuEuL anticancer prodrug over some existing ones and open the way for decisive improvements in multipurpose prodrugs.

  13. Influence of crosslinking on the mechanical behavior of 3D printed alginate scaffolds: Experimental and numerical approaches.

    Science.gov (United States)

    Naghieh, Saman; Karamooz-Ravari, Mohammad Reza; Sarker, M D; Karki, Eva; Chen, Xiongbiao

    2018-04-01

    Tissue scaffolds fabricated by three-dimensional (3D) bioprinting are attracting considerable attention for tissue engineering applications. Because the mechanical properties of hydrogel scaffolds should match the damaged tissue, changing various parameters during 3D bioprinting has been studied to manipulate the mechanical behavior of the resulting scaffolds. Crosslinking scaffolds using a cation solution (such as CaCl 2 ) is also important for regulating the mechanical properties, but has not been well documented in the literature. Here, the effect of varied crosslinking agent volume and crosslinking time on the mechanical behavior of 3D bioplotted alginate scaffolds was evaluated using both experimental and numerical methods. Compression tests were used to measure the elastic modulus of each scaffold, then a finite element model was developed and a power model used to predict scaffold mechanical behavior. Results showed that crosslinking time and volume of crosslinker both play a decisive role in modulating the mechanical properties of 3D bioplotted scaffolds. Because mechanical properties of scaffolds can affect cell response, the findings of this study can be implemented to modulate the elastic modulus of scaffolds according to the intended application. Copyright © 2018 Elsevier Ltd. All rights reserved.

  14. Experimental and numerical approaches of the hydro-mechanical behaviour of a quasi-saturated compacted clayey soil

    Directory of Open Access Journals (Sweden)

    Li Zhong-Sen

    2016-01-01

    Full Text Available The present research is funded by the French National Project « TerreDurable », which is dedicated to the study of soils in quasi-saturated conditions (close to saturation for the analysis of stability and settlement of earth structures such as embankment, dams. A global presentation of the drying-wetting test shows the volume change, air entry and soil-water characteristics of the soil at slurry and oven-dried conditions. Unsaturated undrained triaxial test was carried out in order to investigate the variation of pore-water pressure from quasi-saturated domain to saturation. The experimental results of the triaxial test are then modeled using a two-dimensional explicit finite difference program (Flac 2D. A constitutive law developed in the TerreDurable project allows better understanding the behaviour of quasi-saturated soils using the water retention curve of quasi-saturated domain proposed by Boutonnier (2007, 2010. A simple effective stress model is used (Cam Clay by taking into account both the suction and the compressibility of equivalent fluid (water + air. The results from numerical calculation and experimental measurements are compared.

  15. Numerical simulation of machining distortions on a forged aerospace component following a one and a multi-step approaches

    Science.gov (United States)

    Prete, Antonio Del; Franchi, Rodolfo; Antermite, Fabrizio; Donatiello, Iolanda

    2018-05-01

    Residual stresses appear in a component as a consequence of thermo-mechanical processes (e.g. ring rolling process) casting and heat treatments. When machining these kinds of components, distortions arise due to the redistribution of residual stresses due to the foregoing process history inside the material. If distortions are excessive, they can lead to a large number of scrap parts. Since dimensional accuracy can affect directly the engines efficiency, the dimensional control for aerospace components is a non-trivial issue. In this paper, the problem related to the distortions of large thin walled aeroengines components in nickel superalloys has been addressed. In order to estimate distortions on inner diameters after internal turning operations, a 3D Finite Element Method (FEM) analysis has been developed on a real industrial test case. All the process history, has been taken into account by developing FEM models of ring rolling process and heat treatments. Three different strategies of ring rolling process have been studied and the combination of related parameters which allows to obtain the best dimensional accuracy has been found. Furthermore, grain size evolution and recrystallization phenomena during manufacturing process has been numerically investigated using a semi empirical Johnson-Mehl-Avrami-Kohnogorov (JMAK) model. The volume subtractions have been simulated by boolean trimming: a one step and a multi step analysis have been performed. The multi-step procedure has allowed to choose the best material removal sequence in order to reduce machining distortions.

  16. Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: design, synthesis, pharmacological investigations and docking studies.

    Science.gov (United States)

    Abdel-Azeem, Ahmed Z; Abdel-Hafez, Atef A; El-Karamany, Gamal S; Farag, Hassan H

    2009-05-15

    The discovery of the inducible isoform of cyclooxygenase enzyme (COX-2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New chlorzoxazone ester prodrugs (6-8) of some acidic NSAIDs (1-3) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (6-8) were confirmed by IR, (1)H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. In vitro chemical stability revealed that the synthesized ester prodrugs (6-8) are chemically stable in hydrochloric acid buffer pH 1.2 as a non-enzymatic simulated gastric fluid (SGF) and in phosphate buffer pH 7.4 as non-enzymatic simulated intestinal fluid (SIF). In 80% human plasma, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis at relatively faster rate (t(1/2) approximately 37 and 34 min for prodrugs 6 and 7, respectively). Mutual ester prodrugs (6-8) were evaluated for their anti-inflammatory and muscle relaxation activities. Scanning electromicrographs of the stomach showed that the ester prodrugs induced very little irritancy in the gastric mucosa of rats after oral administration for 4days. In addition, docking of the mutual ester prodrugs (6-8) into COX-2 active site was conducted in order to predict the affinity and orientation of these prodrugs at the enzyme active site.

  17. The Role of Bystander Effects in the Antitumor Activity of the Hypoxia-Activated Prodrug PR-104

    Science.gov (United States)

    Foehrenbacher, Annika; Patel, Kashyap; Abbattista, Maria R.; Guise, Chris P.; Secomb, Timothy W.; Wilson, William R.; Hicks, Kevin O.

    2013-01-01

    Activation of prodrugs in tumors (e.g., by bioreduction in hypoxic zones) has the potential to generate active metabolites that can diffuse within the tumor microenvironment. Such “bystander effects” may offset spatial heterogeneity in prodrug activation but the relative importance of this effect is not understood. Here, we quantify the contribution of bystander effects to antitumor activity for the first time, by developing a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) model for PR-104, a phosphate ester pre-prodrug that is converted systemically to the hypoxia-activated prodrug PR-104A. Using Green’s function methods we calculated concentrations of oxygen, PR-104A and its active metabolites, and resultant cell killing, at each point of a mapped three-dimensional tumor microregion. Model parameters were determined in vitro, using single cell suspensions to determine relationships between PR-104A metabolism and clonogenic cell killing, and multicellular layer (MCL) cultures to measure tissue diffusion coefficients. LC-MS/MS detection of active metabolites in the extracellular medium following exposure of anoxic single cell suspensions and MCLs to PR-104A confirmed that metabolites can diffuse out of cells and through a tissue-like environment. The SR-PK/PD model estimated that bystander effects contribute 30 and 50% of PR-104 activity in SiHa and HCT116 tumors, respectively. Testing the model by modulating PR-104A-activating reductases and hypoxia in tumor xenografts showed overall clonogenic killing broadly consistent with model predictions. Overall, our data suggest that bystander effects are important in PR-104 antitumor activity, although their reach may be limited by macroregional heterogeneity in hypoxia and reductase expression in tumors. The reported computational and experimental techniques are broadly applicable to all targeted anticancer prodrugs and could be used to identify strategies for rational prodrug optimization. PMID

  18. The Design and Evaluation of an l-Dopa–Lazabemide Prodrug for the Treatment of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Monique Hoon

    2017-11-01

    Full Text Available l-Dopa, the metabolic precursor of dopamine, is the treatment of choice for the symptomatic relief of the advanced stages of Parkinson’s disease. The oral bioavailability of l-dopa, however, is only about 10% to 30%, and less than 1% of the oral dose is estimated to reach the brain unchanged. l-Dopa’s physicochemical properties are responsible for its poor bioavailability, short half-life and the wide range of inter- and intrapatient variations of plasma levels. An l-dopa–lazabemide prodrug is proposed to overcome the problems associated with l-dopa absorption. Lazabemide is a monoamine oxidase (MAO-B inhibitor, a class of compounds that slows the depletion of dopamine stores in Parkinson’s disease and elevates dopamine levels produced by exogenously administered l-dopa. l-Dopa was linked at the carboxylate with the primary aminyl functional group of lazabemide via an amide, a strategy which is anticipated to protect l-dopa against peripheral decarboxylation and possibly also enhance the membrane permeability of the prodrug. Selected physicochemical and biochemical properties of the prodrug were determined and included lipophilicity (logD, solubility, passive diffusion permeability, pKa, chemical and metabolic stability as well as cytotoxicity. Although oral and i.p. treatment of mice with the prodrug did not result in enhanced striatal dopamine levels, 3,4-dihydroxyphenylacetic acid (DOPAC levels were significantly depressed compared to saline, l-dopa and carbidopa/l-dopa treatment. Based on the results, further preclinical evaluation of the l-dopa–lazabemide prodrug should be undertaken with the aim of discovering prodrugs that may be advanced to the clinical stages of development.

  19. Assessing the Impacts of Flooding Caused by Extreme Rainfall Events Through a Combined Geospatial and Numerical Modeling Approach

    Science.gov (United States)

    Santillan, J. R.; Amora, A. M.; Makinano-Santillan, M.; Marqueso, J. T.; Cutamora, L. C.; Serviano, J. L.; Makinano, R. M.

    2016-06-01

    In this paper, we present a combined geospatial and two dimensional (2D) flood modeling approach to assess the impacts of flooding due to extreme rainfall events. We developed and implemented this approach to the Tago River Basin in the province of Surigao del Sur in Mindanao, Philippines, an area which suffered great damage due to flooding caused by Tropical Storms Lingling and Jangmi in the year 2014. The geospatial component of the approach involves extraction of several layers of information such as detailed topography/terrain, man-made features (buildings, roads, bridges) from 1-m spatial resolution LiDAR Digital Surface and Terrain Models (DTM/DSMs), and recent land-cover from Landsat 7 ETM+ and Landsat 8 OLI images. We then used these layers as inputs in developing a Hydrologic Engineering Center Hydrologic Modeling System (HEC HMS)-based hydrologic model, and a hydraulic model based on the 2D module of the latest version of HEC River Analysis System (RAS) to dynamically simulate and map the depth and extent of flooding due to extreme rainfall events. The extreme rainfall events used in the simulation represent 6 hypothetical rainfall events with return periods of 2, 5, 10, 25, 50, and 100 years. For each event, maximum flood depth maps were generated from the simulations, and these maps were further transformed into hazard maps by categorizing the flood depth into low, medium and high hazard levels. Using both the flood hazard maps and the layers of information extracted from remotely-sensed datasets in spatial overlay analysis, we were then able to estimate and assess the impacts of these flooding events to buildings, roads, bridges and landcover. Results of the assessments revealed increase in number of buildings, roads and bridges; and increase in areas of land-cover exposed to various flood hazards as rainfall events become more extreme. The wealth of information generated from the flood impact assessment using the approach can be very useful to the

  20. Statistical characteristics of falling-film flows: A synergistic approach at the crossroads of direct numerical simulations and experiments

    Science.gov (United States)

    Charogiannis, Alexandros; Denner, Fabian; van Wachem, Berend G. M.; Kalliadasis, Serafim; Markides, Christos N.

    2017-12-01

    We scrutinize the statistical characteristics of liquid films flowing over an inclined planar surface based on film height and velocity measurements that are recovered simultaneously by application of planar laser-induced fluorescence (PLIF) and particle tracking velocimetry (PTV), respectively. Our experiments are complemented by direct numerical simulations (DNSs) of liquid films simulated for different conditions so as to expand the parameter space of our investigation. Our statistical analysis builds upon a Reynolds-like decomposition of the time-varying flow rate that was presented in our previous research effort on falling films in [Charogiannis et al., Phys. Rev. Fluids 2, 014002 (2017), 10.1103/PhysRevFluids.2.014002], and which reveals that the dimensionless ratio of the unsteady term to the mean flow rate increases linearly with the product of the coefficients of variation of the film height and bulk velocity, as well as with the ratio of the Nusselt height to the mean film height, both at the same upstream PLIF/PTV measurement location. Based on relations that are derived to describe these results, a methodology for predicting the mass-transfer capability (through the mean and standard deviation of the bulk flow speed) of these flows is developed in terms of the mean and standard deviation of the film thickness and the mean flow rate, which are considerably easier to obtain experimentally than velocity profiles. The errors associated with these predictions are estimated at ≈1.5 % and 8% respectively in the experiments and at <1 % and <2 % respectively in the DNSs. Beyond the generation of these relations for the prediction of important film flow characteristics based on simple flow information, the data provided can be used to design improved heat- and mass-transfer equipment reactors or other process operation units which exploit film flows, but also to develop and validate multiphase flow models in other physical and technological settings.

  1. A multiscale approach to determine hydraulic conductivity in thick claystone aquitards using field, laboratory, and numerical modeling methods

    Science.gov (United States)

    Smith, L. A.; Barbour, S. L.; Hendry, M. J.; Novakowski, K.; van der Kamp, G.

    2016-07-01

    Characterizing the hydraulic conductivity (K) of aquitards is difficult due to technical and logistical difficulties associated with field-based methods as well as the cost and challenge of collecting representative and competent core samples for laboratory analysis. The objective of this study was to produce a multiscale comparison of vertical and horizontal hydraulic conductivity (Kv and Kh, respectively) of a regionally extensive Cretaceous clay-rich aquitard in southern Saskatchewan. Ten vibrating wire pressure transducers were lowered into place at depths between 25 and 325 m, then the annular was space was filled with a cement-bentonite grout. The in situ Kh was estimated at the location of each transducer by simulating the early-time pore pressure measurements following setting of the grout using a 2-D axisymmetric, finite element, numerical model. Core samples were collected during drilling for conventional laboratory testing for Kv to compare with the transducer-determined in situ Kh. Results highlight the importance of scale and consideration of the presence of possible secondary features (e.g., fractures) in the aquitard. The proximity of the transducers to an active potash mine (˜1 km) where depressurization of an underlying aquifer resulted in drawdown through the aquitard provided a unique opportunity to model the current hydraulic head profile using both the Kh and Kv estimates. Results indicate that the transducer-determined Kh estimates would allow for the development of the current hydraulic head distribution, and that simulating the pore pressure recovery can be used to estimate moderately low in situ Kh (<10-11 m s-1).

  2. Leakage detection of Marcellus Shale natural gas at an Upper Devonian gas monitoring well: a 3-d numerical modeling approach.

    Science.gov (United States)

    Zhang, Liwei; Anderson, Nicole; Dilmore, Robert; Soeder, Daniel J; Bromhal, Grant

    2014-09-16

    Potential natural gas leakage into shallow, overlying formations and aquifers from Marcellus Shale gas drilling operations is a public concern. However, before natural gas could reach underground sources of drinking water (USDW), it must pass through several geologic formations. Tracer and pressure monitoring in formations overlying the Marcellus could help detect natural gas leakage at hydraulic fracturing sites before it reaches USDW. In this study, a numerical simulation code (TOUGH 2) was used to investigate the potential for detecting leaking natural gas in such an overlying geologic formation. The modeled zone was based on a gas field in Greene County, Pennsylvania, undergoing production activities. The model assumed, hypothetically, that methane (CH4), the primary component of natural gas, with some tracer, was leaking around an existing well between the Marcellus Shale and the shallower and lower-pressure Bradford Formation. The leaky well was located 170 m away from a monitoring well, in the Bradford Formation. A simulation study was performed to determine how quickly the tracer monitoring could detect a leak of a known size. Using some typical parameters for the Bradford Formation, model results showed that a detectable tracer volume fraction of 2.0 × 10(-15) would be noted at the monitoring well in 9.8 years. The most rapid detection of tracer for the leak rates simulated was 81 days, but this scenario required that the leakage release point was at the same depth as the perforation zone of the monitoring well and the zones above and below the perforation zone had low permeability, which created a preferred tracer migration pathway along the perforation zone. Sensitivity analysis indicated that the time needed to detect CH4 leakage at the monitoring well was very sensitive to changes in the thickness of the high-permeability zone, CH4 leaking rate, and production rate of the monitoring well.

  3. Leveraging Hypoxia-Activated Prodrugs to Prevent Drug Resistance in Solid Tumors.

    Directory of Open Access Journals (Sweden)

    Danika Lindsay

    2016-08-01

    Full Text Available Experimental studies have shown that one key factor in driving the emergence of drug resistance in solid tumors is tumor hypoxia, which leads to the formation of localized environmental niches where drug-resistant cell populations can evolve and survive. Hypoxia-activated prodrugs (HAPs are compounds designed to penetrate to hypoxic regions of a tumor and release cytotoxic or cytostatic agents; several of these HAPs are currently in clinical trial. However, preliminary results have not shown a survival benefit in several of these trials. We hypothesize that the efficacy of treatments involving these prodrugs depends heavily on identifying the correct treatment schedule, and that mathematical modeling can be used to help design potential therapeutic strategies combining HAPs with standard therapies to achieve long-term tumor control or eradication. We develop this framework in the specific context of EGFR-driven non-small cell lung cancer, which is commonly treated with the tyrosine kinase inhibitor erlotinib. We develop a stochastic mathematical model, parametrized using clinical and experimental data, to explore a spectrum of treatment regimens combining a HAP, evofosfamide, with erlotinib. We design combination toxicity constraint models and optimize treatment strategies over the space of tolerated schedules to identify specific combination schedules that lead to optimal tumor control. We find that (i combining these therapies delays resistance longer than any monotherapy schedule with either evofosfamide or erlotinib alone, (ii sequentially alternating single doses of each drug leads to minimal tumor burden and maximal reduction in probability of developing resistance, and (iii strategies minimizing the length of time after an evofosfamide dose and before erlotinib confer further benefits in reduction of tumor burden. These results provide insights into how hypoxia-activated prodrugs may be used to enhance therapeutic effectiveness in the

  4. Fracture in quasi-brittle materials: experimental and numerical approach for the determination of an incremental model with generalized variables

    International Nuclear Information System (INIS)

    Morice, Erwan

    2014-01-01

    Fracture in quasi-brittle materials, such as ceramics or concrete, can be represented schematically by series of events of nucleation and coalescence of micro-cracks. Modeling this process is an important challenge for the reliability and life prediction of concrete structures, in particular the prediction of the permeability of damaged structures. A multi-scale approach is proposed. The global behavior is modeled within the fracture mechanics framework and the local behavior is modeled by the discrete element method. An approach was developed to condense the non linear behavior of the mortar. A model reduction technic is used to extract the relevant information from the discrete elements method. To do so, the velocity field is partitioned into mode I, II, linear and non-linear components, each component being characterized by an intensity factor and a fixed spatial distribution. The response of the material is hence condensed in the evolution of the intensity factors, used as non-local variables. A model was also proposed to predict the behavior of the crack for proportional and non-proportional mixed mode I+II loadings. An experimental campaign was finally conducted to characterize the fatigue and fracture behavior of mortar. The results show that fatigue crack growth can be of significant importance. The experimental velocity field determined, in the crack tip region, by DIC, were analyzed using the same technic as that used for analyzing the fields obtained by the discrete element method showing consistent results. (author)

  5. In vivo evaluation of lipid-based formulations for oral delivery of apomorphine and its diester prodrugs

    DEFF Research Database (Denmark)

    Borkar, Nrupa Nitin; Holm, René; Yang, Mingshi

    2016-01-01

    .05) than after DLA-w/o administration, indicating that triglycerides and surfactants improved the oral absorption of DLA. Similarly, Cmax and AUC after dosing apomorphine-o/w were significantly higher (p≤0.05) than that of aqueous suspension. This suggested that lipids and lipolysis products possibly aided......In the present study, the differences in oral absorption of apomorphine and its diester prodrugs and the effect of lipid-based formulations on the absorption of apomorphine or its prodrugs were investigated. Apomorphine, dilauroyl apomorphine (DLA) and dipalmitoyl apomorphine (DPA) were orally...

  6. Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy

    DEFF Research Database (Denmark)

    Denmeade, Samuel R; Mhaka, Annastasiah M; Rosen, D Marc

    2012-01-01

    adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment...... of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host...

  7. Stability and in vitro metabolism of dipeptide model prodrugs with affinity for the oligopeptide transporter

    DEFF Research Database (Denmark)

    Lepist, E I; Kusk, T; Larsen, D H

    2000-01-01

    into the blood circulation and/or by its site of action. In these kinds of prodrugs the ester linkage may be broken by pH dependent and/or enzyme catalyzed hydrolysis. The objective of the present study was to investigate the degradation mechanism and rate of the model compounds Glu(OBzl)-Sar, D...... on buffer concentration, temperature, pH, and ionic strength. In biological media such as 80% human plasma, human gastric juice and intestinal fluid, and 10% rat jejunal homogenate at 37 degrees C, the half-lives were greater than 1 h except for the hydrolysis of Glu(OBzl)-Sar in 10% rat jejunal homogenate...

  8. Dynamic behaviour of a planar micro-beam loaded by a fluid-gap: Analytical and numerical approach in a high frequency range, benchmark solutions

    Science.gov (United States)

    Novak, A.; Honzik, P.; Bruneau, M.

    2017-08-01

    Miniaturized vibrating MEMS devices, active (receivers or emitters) or passive devices, and their use for either new applications (hearing, meta-materials, consumer devices,…) or metrological purposes under non-standard conditions, are involved today in several acoustic domains. More in-depth characterisation than the classical ones available until now are needed. In this context, the paper presents analytical and numerical approaches for describing the behaviour of three kinds of planar micro-beams of rectangular shape (suspended rigid or clamped elastic planar beam) loaded by a backing cavity or a fluid-gap, surrounded by very thin slits, and excited by an incident acoustic field. The analytical approach accounts for the coupling between the vibrating structure and the acoustic field in the backing cavity, the thermal and viscous diffusion processes in the boundary layers in the slits and the cavity, the modal behaviour for the vibrating structure, and the non-uniformity of the acoustic field in the backing cavity which is modelled in using an integral formulation with a suitable Green's function. Benchmark solutions are proposed in terms of beam motion (from which the sensitivity, input impedance, and pressure transfer function can be calculated). A numerical implementation (FEM) is handled against which the analytical results are tested.

  9. Earthquake induced variations in extrusion rate: A numerical modeling approach to the 2006 eruption of Merapi Volcano (Indonesia)

    Science.gov (United States)

    Carr, Brett B.; Clarke, Amanda B.; de'Michieli Vitturi, Mattia

    2018-01-01

    Extrusion rates during lava dome-building eruptions are variable and eruption sequences at these volcanoes generally have multiple phases. Merapi Volcano, Java, Indonesia, exemplifies this common style of activity. Merapi is one of Indonesia's most active volcanoes and during the 20th and early 21st centuries effusive activity has been characterized by long periods of very slow (work has suggested that the peak extrusion rates observed in early June were triggered by the earthquake through either dynamic stress-induced overpressure or the addition of CO2 due to decarbonation and gas escape from new fractures in the bedrock. We use the numerical model to test the feasibility of these proposed hypotheses and show that, in order to explain the observed change in extrusion rate, an increase of approximately 5-7 MPa in magma storage zone overpressure is required. We also find that the addition of ∼1000 ppm CO2 to some portion of the magma in the storage zone following the earthquake reduces water solubility such that gas exsolution is sufficient to generate the required overpressure. Thus, the proposed mechanism of CO2 addition is a viable explanation for the peak phase of the Merapi 2006 eruption. A time-series of extrusion rate shows a sudden increase three days following the earthquake. We explain this three-day delay by the combined time required for the effects of the earthquake and corresponding CO2 increase to develop in the magma storage system (1-2 days), and the time we calculate for the affected magma to ascend from storage zone to surface (40 h). The increased extrusion rate was sustained for 2-7 days before dissipating and returning to pre-earthquake levels. During this phase, we estimate that 3.5 million m3 DRE of magma was erupted along with 11 ktons of CO2. The final phase of the 2006 eruption was characterized by highly variable extrusion rates. We demonstrate that those changes were likely controlled by failure of the edifice that had been confining

  10. Numerical analysis

    CERN Document Server

    Khabaza, I M

    1960-01-01

    Numerical Analysis is an elementary introduction to numerical analysis, its applications, limitations, and pitfalls. Methods suitable for digital computers are emphasized, but some desk computations are also described. Topics covered range from the use of digital computers in numerical work to errors in computations using desk machines, finite difference methods, and numerical solution of ordinary differential equations. This book is comprised of eight chapters and begins with an overview of the importance of digital computers in numerical analysis, followed by a discussion on errors in comput

  11. Numerical relativity

    CERN Document Server

    Shibata, Masaru

    2016-01-01

    This book is composed of two parts: First part describes basics in numerical relativity, that is, the formulations and methods for a solution of Einstein's equation and general relativistic matter field equations. This part will be helpful for beginners of numerical relativity who would like to understand the content of numerical relativity and its background. The second part focuses on the application of numerical relativity. A wide variety of scientific numerical results are introduced focusing in particular on the merger of binary neutron stars and black holes.

  12. Numerical and Experimental Approach to Investigate Plane-view Shape and Crop Loss in Multistage Plate Rolling

    International Nuclear Information System (INIS)

    Byon, Sang Min

    2013-01-01

    A finite element based approach that can be used to investigate the plane-view shape and crop loss of a material during plate rolling is presented. We employed a three-dimensional finite element model to continuously simulate the shape change of the head and tail of a plate as the number of rolling passes increases. The main feature of the proposed model lies in the fact that the multistage rolling can be simulated without a break because the rolling direction of the material is reversibly controlled as the roll gap sequentially decreases. The material constants required in the finite element analysis were experimentally obtained by hot tensile tests. We also performed a pilot hot plate rolling test to verify the usefulness of the proposed finite element model. Results reveal that the computed plane-view shapes as well as crop losses by the proposed finite element model were in good agreement with the measured ones. The crop losses predicted by the proposed model were within 5% of those measured from the pilot hot plate rolling test

  13. The nitric oxide prodrug JS-K and its structural analogues as cancer therapeutic agents.

    Science.gov (United States)

    Maciag, Anna E; Saavedra, Joseph E; Chakrapani, Harinath

    2009-09-01

    Nitric oxide (NO) prodrugs of the diazeniumdiolate class are routinely used as reliable sources of nitric oxide in chemical and biological laboratory settings. O(2)-(2,4-dinitrophenyl) diazeniumdiolates, which are derivatized forms of ionic diazeniumdiolates, have been found to show potent anti-proliferative activity in a variety of cancer cells, presumably through the effects of NO. One important member of this class of diazeniumdiolates, O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K), has shown promise as a novel cancer therapeutic agent in a number of animal models. This review describes the developments in chemical and biochemical characterization and structure-activity relationship of JS-K and its analogues. In addition, some molecular mechanistic insights into the observed anti-proliferative activity of JS-K are discussed. Finally, a structural motif is presented for O(2)-(aryl) diazeniumdiolate nitric oxide prodrugs that show potency comparable with that of JS-K.

  14. Mefenamic acid conjugates based on a hydrophilic biopolymer hydroxypropylcellulose: novel prodrug design, characterization and thermal analysis

    International Nuclear Information System (INIS)

    Hussain, M.A.; Kausar, R.; Amin, M.

    2015-01-01

    Macromolecular prodrugs (MPDs) of mefenamic acid were designed onto a cellulose ether derivative hydroxypropylcellulose (HPC) as ester conjugates. Fabrication of HPC-mefenamic acid conjugates was achieved by using p-toluenesulfonyl chloride as carboxylic acid (a functional group in drug) activator at 80 degree C for 24 h under nitrogen atmosphere. Reaction was preceded under homogeneous reaction conditions as HPC was dissolved before use in DMAc solvent. Imidazole was used as a base. Easy workup reactions resulted in good yields (55-65%) and degree of substitution (DS) of drug (0.37-0.99) onto HPC. The DS was calculated by acid-base titration after saponification and UV/Vis spectrophotometry after hydrolysis. DS by both of the methods was found in good agreement with each other. Aqueous and organic soluble novel prodrugs of mefenamic acid were purified and characterized by different spectroscopic and thermal analysis techniques. The initial, maximum and final degradation temperatures of HPC, mefenamic acid and HPC-mefenamic acid conjugates were drawn from thermogravimetric (TG) and derivative TG curves and compared to access relative thermal stability. The TG analysis has indicated that samples obtained were thermally more stable especially with increased stability of mefenamic acid in HPC-mefenamic acid conjugates. These novel MPDs of mefenamic acid (i.e., HPC-mefenamic acid conjugates) may have potential applications in pharmaceutically viable drug design due to wide range of solubility and extra thermal stability imparted after MPD formation. (author)

  15. A prodrug strategy based on chitosan for efficient intracellular anticancer drug delivery

    International Nuclear Information System (INIS)

    Chen, Cheng; Zhou, Jiang-Ling; Han, Xue; Song, Fei; Wang, Xiu-Li; Wang, Yu-Zhong

    2014-01-01

    Doxorubicin (DOX), one of the most widely used anticancer drugs, is restricted in clinical application due to its severe side effects and inefficient cellular uptake. To overcome the drawbacks, herein, an endosomal pH-activated prodrug was designed and fabricated by conjugating DOX with chitosan via an acid-cleavable hydrazone bond. The resulting DOX conjugates can self-assemble into nano-sized particles, which were very stable and presented no burst release of DOX at a neutral pH condition. Notably, the nanoparticles exhibited excellent cell uptake properties and a remarkable drug accumulation in tumor cells. Once internalized into the cells, moreover, DOX can be fast released from the nanoparticles, and the release mechanism changed from the anomalous transport at pH 7.4 to the combination pattern of diffusion- and erosion-controlled release at pH 6.0 or 5.0. The prodrugs showed obvious cytotoxicity for HeLa cells with fairly low IC 50 values, offering a new platform for targeted cancer therapy. (papers)

  16. Aspartic acid based nucleoside phosphoramidate prodrugs as potent inhibitors of hepatitis C virus replication.

    Science.gov (United States)

    Maiti, Munmun; Maiti, Mohitosh; Rozenski, Jef; De Jonghe, Steven; Herdewijn, Piet

    2015-05-14

    In view of a persistent threat to mankind, the development of nucleotide-based prodrugs against hepatitis C virus (HCV) is considered as a constant effort in many medicinal chemistry groups. In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity, we have explored, for the first time, aspartic acid (Asp) and iminodiacetic acid (IDA) esters as amidate counterparts by considering three 2'-C-methyl containing nucleosides, 2'-C-Me-cytidine, 2'-C-Me-uridine and 2'-C-Me-2'-fluoro-uridine. Synthesis of these analogues required protection for the vicinal diol functionality of the sugar moiety and the amino group of the cytidine nucleoside to regioselectively perform phosphorylation reaction at the 5'-hydroxyl group. Anti-HCV data demonstrate that the Asp-based phosphoramidates are ∼550 fold more potent than the parent nucleosides. The inhibitory activity of the Asp-ProTides was higher than the Ala-ProTides, suggesting that Asp would be a potential amino acid candidate to be considered for developing novel antiviral prodrugs.

  17. Anti-HIV therapy with AZT prodrugs: AZT phosphonate derivatives, current state and prospects.

    Science.gov (United States)

    Khandazhinskaya, Anastasiya; Matyugina, Elena; Shirokova, Elena

    2010-06-01

    AIDS, a disease caused by human immunodeficiency virus, was called 'plague of the twentieth century'. 3'-Azido-3'-deoxythymidine (AZT), the first compound approved for the treatment of HIV, is still a mandatory component of treatment schemes. However, its toxicity stimulated a search for new agents. This review presents the history and current state of the design of AZT prodrugs based on its phosphonate derivatives. Although every effort was made to include as many AZT structures bearing phosphonate residues and demonstrate the variety they offer, we also concentrated on the studies performed in our laboratory. Special attention was also paid to AZT 5'-H-phosphonate (phosphazide, Nikavir) approved in the Russian Federation as a drug for the prevention and treatment of HIV infection. The prodrug strategy applied to AZT phosphonate derivatives enriched chemistry, biology and medicine not only with new knowledge, methods and structures, but also with a new anti-HIV drug Nikavir. Currently, study of another phosphonate, AZT 5'-aminocarbonylphosphonate, is underway. Slow release of AZT following oral administration and penetration into cells, decreased toxicity and the lack of cumulative properties make the compounds of this group promising as extended-release forms of AZT.

  18. Hypoxia-Inducible Regulation of a Prodrug-Activating Enzyme for Tumor-Specific Gene Therapy

    Directory of Open Access Journals (Sweden)

    Toru Shibata

    2002-01-01

    Full Text Available Previous studies have suggested that tumor hypoxia could be exploited for cancer gene therapy. Using hypoxia-responsive elements derived from the human vascular endothelial growth factor gene, we have generated vectors expressing a bacterial nitroreductase. (20NTR gene that can activate the anticancer prodrug CB1954. Stable transfectants of human HT1080 tumor cells with hypoxia-inducible vectors were established with G418 selection. Hypoxic induction of NTR protein correlated with increased sensitivity to in vitro exposure of HT 1080 cells to the prodrug. Growth delay assays were performed with established tumor xenografts derived from the same cells to detect the in vivo efficacy of CB1954 conversion to its cytotoxic form. Significant antitumor effects were achieved with intraperitoneal injections of CB1954 both in tumors that express NTR constitutively or with a hypoxia-inducible promoter. In addition, respiration of 10% O2 increased tumor hypoxia in vivo and enhanced the antitumor effects. Taken together, these results demonstrate that hypoxia-inducible vectors may be useful for tumor-selective gene therapy, although the problem of delivery of the vector to the tumors, particularly to the hypoxic cells in the tumors, is not addressed by these studies.

  19. Numerical simulation in steam injection wellbores by mechanistic approach; Simulacao numerica do escoamento de vapor em pocos por uma abordagem mecanicista

    Energy Technology Data Exchange (ETDEWEB)

    Souza Junior, J.C. de; Campos, W.; Lopes, D.; Moura, L.S.S. [PETROBRAS, Rio de Janeiro, RJ (Brazil); Thomas, A. Clecio F. [Universidade Estadual do Ceara (UECE), CE (Brazil)

    2008-07-01

    This work addresses to the development of a hydrodynamic and heat transfer mechanistic model for steam flow in injection wellbores. The problem of two-phase steam flow in wellbores has been solved recently by using available empirical correlations from petroleum industry (Lopes, 1986) and nuclear industry (Moura, 1991).The good performance achieved by mechanistic models developed by Ansari (1994), Hasan (1995), Gomez (2000) and Kaya (2001) supports the importance of the mechanistic approach for the steam flow problem in injection wellbores. In this study, the methodology to solve the problem consists in the application of a numerical method to the governing equations of steam flow and a marching algorithm to determine the distribution of the pressure and temperature along the wellbore. So, a computer code has been formulated to get numerical results, which provides a comparative study to the main models found in the literature. Finally, when compared to available field data, the mechanistic model for downward vertical steam flow in wellbores gave better results than the empirical correlations. (author)

  20. Smart activatable and traceable dual-prodrug for image-guided combination photodynamic and chemo-therapy.

    Science.gov (United States)

    Hu, Fang; Yuan, Youyong; Mao, Duo; Wu, Wenbo; Liu, Bin

    2017-11-01

    Activatable photosensitizers (PSs) and chemo-prodrugs are highly desirable for anti-cancer therapy to reduce systemic toxicity. However, it is difficult to integrate both together into a molecular probe for combination therapy due to the complexity of introducing PS, singlet oxygen quencher, chemo-drug, chemo-drug inhibitor and active linker at the same time. To realize activatable PS and chemo-prodrug combination therapy, we develop a smart therapeutic platform in which the chemo-prodrug serves as the singlet oxygen quencher for the PS. Specifically, the photosensitizing activity and fluorescence of the PS (TPEPY-SH) are blocked by the chemo-prodrug (Mitomycin C, MMC) in the probe. Meanwhile, the cytotoxicity of MMC is also inhibited by the electron-withdrawing acyl at the nitrogen position next to the linker. Upon glutathione activation, TPEPY-S-MMC can simultaneously release active PS and MMC for combination therapy. The restored fluorescence of TPEPY-SH is also used to report the activation for both PS and MMC as well as to guide the photodynamic therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.