subject:(ddI)

University of Southern California

1. Bi, Lucun. Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine.

Degree: PhD, Pharmaceutical Sciences, 2008, University of Southern California

URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/47592/rec/3609

► High level of virologic failure was observed in HIV patients receiving combinations of tenofovir (TFV), lamivudine (3TC) combined with either abacavir (ABC) or didanosine (ddI).… (more)

▼ High level of virologic failure was observed in HIV patients receiving combinations of tenofovir (TFV), lamivudine (3TC) combined with either abacavir (ABC) or didanosine (ddI). To investigate the pharmacologic mechanisms involve with the virologic failures, a comprehensive study was undertaken to evaluate the intracellular concentration of the active moiety (ddNTP) of these respective nucleoside analogs.; Triple nucleoside combinations were tested at physiological concentrations revealed reductions of 5 to 33% of the respective ddNTP. In vitro studies evaluating TFV and ABC in a concentration dependent manner showed a reduction of 40% and 30% in intracellular CBV-TP and TFV-DP. Similar findings were demonstrated with TFV and ddI, where 40% and 25% reduction in ddATP and TFV-DP, respectively, was detected. The level of dATP and dGTP, endogenous nucleotides, were increased by 2.4- and 2.7-fold, respectively, when cells were treated with 20 µM TFV, which can dilute the effect of ddNTP.; The expression of MRP2 and MRP4 were increased in cells serially passaged in either ABC or TFV, which correlated with cellular viability in the presence of high concentrations of nucleosides. Moreover, these cells had significantly lower level of ddNTP accumulation as compared to the wild type counterparts.; A clinical study was undertaken to evaluate whether the in vitro findings were also observed in humans. The combination of ABC and TDF resulted in a 2-fold increase in intracellular TFV-DP in patients receiving the combination of ABC and TFV as compared to TDF alone. Increases in TFV-DP may be attributed to higher plasma level of TFV, which was detected in the second phase of this study. A 4-fold increase in CBV-TP was detected three of nine patients, while the other six (6/9) had a 41% reduction. The degree of CBV-TP reduction is consistent with what is seen in vitro.; These findings suggest that cellular adaptive are critical in reducing intracellular levels of nucleoside analogs and their corresponding ddNTP, which may increase risk of virologic failures. The underlying pharmacological mechanisms may include but are not limited to, the competitive inhibition of anabolic enzymes, increase expression of efflux transporters and increase dATP and dGTP, where the resultant effect is reduced antiviral activity. Advisors/Committee Members: Burckart, Gilbert J. (Committee Chair), Louie, Stan (Committee Member), Shen, Wei-Chiang (Committee Member), D'Argenio, David (Committee Member), Wang, Clay C. C. (Committee Member).

Subjects/Keywords: nucleoside analog; NRTI; intracellular drug-drug interaction; efflux transporters; MRP2; MRP4; cellular adaptive response; ddNTP; TFV; ABC; ddI; endogenous nucleotide pools; PNP

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bi, L. (2008). Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/47592/rec/3609

Chicago Manual of Style (16^th Edition):

Bi, Lucun. “Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine.” 2008. Doctoral Dissertation, University of Southern California. Accessed April 11, 2021. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/47592/rec/3609.

MLA Handbook (7^th Edition):

Bi, Lucun. “Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine.” 2008. Web. 11 Apr 2021.

Vancouver:

Bi L. Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine. [Internet] [Doctoral dissertation]. University of Southern California; 2008. [cited 2021 Apr 11]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/47592/rec/3609.

Council of Science Editors:

Bi L. Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine. [Doctoral Dissertation]. University of Southern California; 2008. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/47592/rec/3609

University of Georgia

2. Clark, Teresa Nicole. Quantitative analysis and pharmacokinetics of reverse transcriptase inhibitors in the pregnant rat.

Degree: 2014, University of Georgia

URL: http://hdl.handle.net/10724/21009

► For over two decades there has been a ceaseless search for more effective treatments of HIV/AIDS. Today there are a number of different therapies that… (more)

Subjects/Keywords: Azidouridine; AZDU; Zidovudine; AZT; Abacavir; ABC; Didanosine; DDI; High Performance Liquid Chromatography; HPLC-UV; LC/MS/MS; Pharmacokinetics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Clark, T. N. (2014). Quantitative analysis and pharmacokinetics of reverse transcriptase inhibitors in the pregnant rat. (Thesis). University of Georgia. Retrieved from http://hdl.handle.net/10724/21009

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Clark, Teresa Nicole. “Quantitative analysis and pharmacokinetics of reverse transcriptase inhibitors in the pregnant rat.” 2014. Thesis, University of Georgia. Accessed April 11, 2021. http://hdl.handle.net/10724/21009.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Clark, Teresa Nicole. “Quantitative analysis and pharmacokinetics of reverse transcriptase inhibitors in the pregnant rat.” 2014. Web. 11 Apr 2021.

Vancouver:

Clark TN. Quantitative analysis and pharmacokinetics of reverse transcriptase inhibitors in the pregnant rat. [Internet] [Thesis]. University of Georgia; 2014. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10724/21009.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Clark TN. Quantitative analysis and pharmacokinetics of reverse transcriptase inhibitors in the pregnant rat. [Thesis]. University of Georgia; 2014. Available from: http://hdl.handle.net/10724/21009

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

3. Diego Alberto Ciscato Cusinato. Influência do EPP-AF® na atividade da glicoproteína P e do citocromo P450 em voluntários sadios usando coquetel de marcadores.

Degree: 2017, University of São Paulo

URL: http://www.teses.usp.br/teses/disponiveis/60/60134/tde-23112017-101956/

►

O EPP-AF® é um extrato padronizado de própolis quimicamente caracterizado e com eficácia e segurança pré-clínica estabelecidas. O objetivo principal deste trabalho foi realizar um… (more)

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O EPP-AF® é um extrato padronizado de própolis quimicamente caracterizado e com eficácia e segurança pré-clínica estabelecidas. O objetivo principal deste trabalho foi realizar um ensaio clínico de segurança para avaliar a influência do EPP-AF® na atividade da P-gp e das principais isoformas CYP, através de um teste in vivo tipo coquetel de fármacos marcadores administrados em doses subterapêuticas. Foram investigados 16 voluntários adultos sadios antes e após a exposição a 375 mg de EPP-AF® por via oral durante 15 dias. As amostras seriadas de sangue foram colhidas até 12 h após a administração do coquetel contendo midazolam (0,2 mg), cafeína (10 mg), omeprazol (2 mg), metoprolol (10 mg), losartana (2 mg) e fexofenadina (10 mg). Foram desenvolvidos e validados três métodos analíticos empregando LC-MS/MS para quantificar as concentrações plasmáticas de fexofenadina, losartana, E-3174 (método 1), omeprazol, 5-OH-omeprazol, midazolam, metoprolol, ?-OHmetoprolol (método 2) e cafeína (método 3). Os métodos não apresentaram efeito matriz ou efeito residual e mostraram-se lineares para os analitos nos intervalos de 0,05-20 ng/mL (fexofenadina); 0,03 - 5 ng/mL (losartana e E31-74); 0,1 - 50 ng/mL (omeprazol), 0,3 - 50 ng/mL (5-OH-omeprazol), 0,01 - 10 ng/mL (midazolam), 0,05 - 50 ng/mL (metoprolol e ?- OH-metoprolol) e 5 - 1000 ng/mL (cafeína). Os parâmetros farmacocinéticos dos compostos foram calculados com base nas curvas de concentração plasmática versus tempo (AUC) empregando o programa Phoenix® WinNonlin®. Os valores das razões das AUC0-t e Cmax após e antes da exposição ao EPP-AF®, apresentados como média geométrica (IC90%) foram de 0,74 (0,62 - 0,89) e 0,90 (0,76 - 1,07) para fexofenadina; 0,88 (0,80 - 0,97) e 0,86 (0,76 - 0,98) para losartana; 0,96 (0,83 - 1,11) e 0,91 (0,79 - 1,04) para E-3174; 1,18 (0,91 - 1,54) e 1,21 (0,87- 1,70) para omeprazol; 1,12 (0,95 - 1,31) e 1,22 (0,95 - 1,67) para 5-OHomeprazol; 1,14 (1,03 - 1,28) e 1,21 (1,00 - 1,46) para o midazolam; 1,04 (0,92 - 1,18) e 0,94 (0,80 - 1,12) para o metoprolol; 1,05 (0,99 - 1,12) e 0,99 (0,88 - 1,12) para ?-OH-metoprolol; 0,97 (0,77 - 1,21) e 0,87 (0,69 - 1,11) para a cafeína. Quando observadas as razões metabólicas das AUC0-t E3174/losartana, 5-OH-omeprazol/omeprazol e ?-OHmetoprolol/ metoprolol encontramos, respectivamente, 1,11 (0,98 - 1,25); 0,94 (0,81 - 1,10) e 1,01 (0,88 - 1,16), indicando que, com exceção do CYP2D6, a administração de EPP-AF® nas condições estudadas apresenta potencial para inibição das isoformas CYP2C19 e CYP3A4 e indução das enzimas CYP1A2, CYP2C9 e do transportador de efluxo P-gp, embora as suas magnitudes encontram-se abaixo dos limites definidos pelos órgãos reguladores e portanto não apresentam relevância clínica

EPP-AF® is a standardized extract of propolis chemically characterized and with established pre-clinical efficacy and safety. The main objective of this work was to perform a clinical trial to evaluate the effect of EPP-AF® on P-gp and the major CYP isoforms activity, through an in vivo assay using the…

Advisors/Committee Members: Eduardo Barbosa Coelho, Fabio Carmona, Ana Maria Soares Pereira.

Subjects/Keywords: Coquetel de marcadores; CYP; Doses subterapêuticas; Farmacocinética; Interação; LC-MS/MS; Metabolismo; P-gp; Própolis; CYP; DDI; Drug cocktail; LC-MS/MS; Metabolism; P-gp; Pharmacokinetics; Propolis; Subtherapeutic doses

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cusinato, D. A. C. (2017). Influência do EPP-AF® na atividade da glicoproteína P e do citocromo P450 em voluntários sadios usando coquetel de marcadores. (Doctoral Dissertation). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/60/60134/tde-23112017-101956/

Chicago Manual of Style (16^th Edition):

Cusinato, Diego Alberto Ciscato. “Influência do EPP-AF® na atividade da glicoproteína P e do citocromo P450 em voluntários sadios usando coquetel de marcadores.” 2017. Doctoral Dissertation, University of São Paulo. Accessed April 11, 2021. http://www.teses.usp.br/teses/disponiveis/60/60134/tde-23112017-101956/.

MLA Handbook (7^th Edition):

Cusinato, Diego Alberto Ciscato. “Influência do EPP-AF® na atividade da glicoproteína P e do citocromo P450 em voluntários sadios usando coquetel de marcadores.” 2017. Web. 11 Apr 2021.

Vancouver:

Cusinato DAC. Influência do EPP-AF® na atividade da glicoproteína P e do citocromo P450 em voluntários sadios usando coquetel de marcadores. [Internet] [Doctoral dissertation]. University of São Paulo; 2017. [cited 2021 Apr 11]. Available from: http://www.teses.usp.br/teses/disponiveis/60/60134/tde-23112017-101956/.

Council of Science Editors:

Cusinato DAC. Influência do EPP-AF® na atividade da glicoproteína P e do citocromo P450 em voluntários sadios usando coquetel de marcadores. [Doctoral Dissertation]. University of São Paulo; 2017. Available from: http://www.teses.usp.br/teses/disponiveis/60/60134/tde-23112017-101956/

4. Dupin, Lucie. Validation et criblage de nouvelles molécules anti-infectieuses sur microarray : applications à Pseudomonas aeruginosa : Validation and screening of new anti-infective molecules on microarray : applications to Pseudomonas aeruginosa.

Degree: Docteur es, Ingénierie pour le vivant, 2016, Lyon

URL: http://www.theses.fr/2016LYSEC018

►

Pseudomonas aeruginosa (PA) est la troisième bactérie impliquée dans les maladies nosocomiales et est la principale cause de mortalité des patients atteints de la mucoviscidose.… (more)

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Pseudomonas aeruginosa (PA) est la troisième bactérie impliquée dans les maladies nosocomiales et est la principale cause de mortalité des patients atteints de la mucoviscidose. PA est résistante à la plupart des traitements antibiotiques. Trouver de nouvelles stratégies thérapeutiques est devenu un enjeu majeur de santé publique, l’une d’entre elles est l’inhibition de facteurs de virulence. Parmi ceux-ci, les lectines sont des protéines impliquées dans l’adhésion et la formation de biofilm via des interactions avec des sucres (PA-IL, PA- IIL, FliC, FliD, PilA, PilY1 et CupB6).Le but de ce travail est donc de trouver des leurres moléculaires ayant une forte affinité pour ces lectines. Ceux-ci sont des motifs saccharidiques présentés de façon multivalente : glycoclusters. De part leur grande diversité structurale et leur faible quantité, un outil de criblage innovant a été développé qui consiste en une lame de verre microstructurée : le glycocluster-microarray. Les glycoclusters sont immobilisés de manière ordonnée par DNA Directed Immobilization (DDI). Deux méthodes de criblage ont été développées grâce à cet outils : 1) le criblage en solution et par compétition d’une bibliothèque de motifs saccharidiques et 2) le criblage d’une bibliothèque de glycoclusters immobilisés sur le microarray. Avec cet outil, des protocoles de mesures d’IC50 et de Kd ont aussi été fiabilisés pour caractériser les meilleurs candidats inhibiteurs des lectines. Le glycocluster- microarray présente l’avantage de n’utiliser qu’une très faible quantité de matériel (quelques picomoles) et permet de réaliser diverses analyses en parallèle.Afin de valider cet outil, une étude sur l’impact de la densité de surface en glycocluster a été menée. Le criblage de plus de 150 motifs saccharidiques a permis de sélectionner ceux ayant une forte affinité pour les lectines. L’analyse sur microarray complétée par de la modélisation moléculaire d’une bibliothèque de glycoclusters, possédant ces motifs et différentes topologies, valences et propriétés (aromaticité, charge,…), a permis d’identifier les paramètres clés dirigeant les relations structure-affinité. Une activité anti-biofilm chez PA a été démontrée avec les meilleurs glycoclusters ciblant PA-IL.Tester l’activité in vivo, chez l’animal, des meilleurs candidats est une voie à explorer. Cibler d’autres lectines comme celles présentes sur le flagelle et les pili de PA et notamment impliquées dans son adhésion précoce est aussi une voie à développer. Pour cela, des tests préliminaires ont été présentés et d’autres sont en cours faisant appel à l’utilisation de bactéries entières ainsi qu’à une détection sans marquage des lectines.

Summary: Pseudomonas aeruginosa (PA) is the third pathogen involved in nosocomial diseases and the major cause of mortality of cystic fibrosis patients. PA develops resistance to antibiotics treatments. And so, developing new therapeutic strategies is a public health issue. One of the promising strategies is to inhibit virulence factors involved in the adhesion and the…

Advisors/Committee Members: Chevolot, Yann (thesis director).

Subjects/Keywords: Interaction glycocluster/lectine; Microarray; DNA Directed Immobilization (DDI); Modélisation moléculaire; Glycocluster/lectin interaction; Microarray; DNA Directed Immobilization (DDI); Molecular simulations

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Dupin, L. (2016). Validation et criblage de nouvelles molécules anti-infectieuses sur microarray : applications à Pseudomonas aeruginosa : Validation and screening of new anti-infective molecules on microarray : applications to Pseudomonas aeruginosa. (Doctoral Dissertation). Lyon. Retrieved from http://www.theses.fr/2016LYSEC018

Chicago Manual of Style (16^th Edition):

Dupin, Lucie. “Validation et criblage de nouvelles molécules anti-infectieuses sur microarray : applications à Pseudomonas aeruginosa : Validation and screening of new anti-infective molecules on microarray : applications to Pseudomonas aeruginosa.” 2016. Doctoral Dissertation, Lyon. Accessed April 11, 2021. http://www.theses.fr/2016LYSEC018.

MLA Handbook (7^th Edition):

Dupin, Lucie. “Validation et criblage de nouvelles molécules anti-infectieuses sur microarray : applications à Pseudomonas aeruginosa : Validation and screening of new anti-infective molecules on microarray : applications to Pseudomonas aeruginosa.” 2016. Web. 11 Apr 2021.

Vancouver:

Dupin L. Validation et criblage de nouvelles molécules anti-infectieuses sur microarray : applications à Pseudomonas aeruginosa : Validation and screening of new anti-infective molecules on microarray : applications to Pseudomonas aeruginosa. [Internet] [Doctoral dissertation]. Lyon; 2016. [cited 2021 Apr 11]. Available from: http://www.theses.fr/2016LYSEC018.

Council of Science Editors:

Dupin L. Validation et criblage de nouvelles molécules anti-infectieuses sur microarray : applications à Pseudomonas aeruginosa : Validation and screening of new anti-infective molecules on microarray : applications to Pseudomonas aeruginosa. [Doctoral Dissertation]. Lyon; 2016. Available from: http://www.theses.fr/2016LYSEC018

5. Goudot, Alice. Développement d'une plateforme de criblage pour la recherche de nouvelles molécules anti-infectieuses : applications à Pseudomonas aeruginosa. : Glycoarray technology development for new anti-infective molecules discovering : applications to Pseudomonas aeruginosa.

Degree: Docteur es, STIC santé et micro et nano-technologies, 2013, Ecully, Ecole centrale de Lyon

URL: http://www.theses.fr/2013ECDL0023

►

Pseudomonas aeruginosa (PA) est l’un des principaux germes impliqués dans les maladies nosocomiales et est aussi la principale cause de mortalité et morbidité des patients… (more)

▼

Pseudomonas aeruginosa (PA) est l’un des principaux germes impliqués dans les maladies nosocomiales et est aussi la principale cause de mortalité et morbidité des patients atteints de la mucoviscidose malgré l’utilisation massive d’antibiotiques. Dans la lutte contre PA, une alternative aux antibiotiques est l’inhibition de ses facteurs de virulence notamment ceux impliqués dans l’adhésion et la formation du biofilm via des interactions de type sucres/protéines. Ces protéines sont appelées lectines (PA-IL, PA-IIL, FliD). L’objectif de ce travail est la recherche de molécules inhibitrices (glycoclusters) de ces lectines impliquées dans la virulence de PA. Compte tenu du grand nombre de glycoclusters à tester et des faibles quantités de matériels biologiques disponibles, un outil de criblage innovant a été développé (glycoarray) à partir d’une lame de verre microstructurée et fonctionnalisée chimiquement afin d’immobiliser de manière organisée et ordonnée les glycoclusters. La méthode d’immobilisation choisie est la méthode d’immobilisation spécifique par hybridation de l’ADN appelée DDI : DNA Directed Immobilization. Sur ces glycoarrays, 3 méthodes indépendantes (lecture de fluorescence directe, IC50 et Kd) de mesure des interactions glycoclusters/lectines ont été mises au point et validées par une étude comparative donnant un classement similaire des glycoclusters pour leur affinité vis-à-vis des lectines Il faut noter que ces mesures faites sur glycoarrays ne consomment que quelques picomoles de glycoclusters comparées aux méthodes classiques (ITC, ELLA, RMN, …) qui nécessitent des micromoles de produits. A l’aide de ces glycoarrays, un criblage d’une bibliothèque d’une centaine de glycoclusters multivalents, de différentes topologies, charges et linkers a permis d’identifier deux structures montrant une très forte affinité vis-à-vis des lectines de PA. Ces glycoclusters sont actuellement en test in vitro et in vivo. Ces études d’interactions sur DDI-glycoarray ont été étendues à d’autres agents pathogènes tels que les bactéries Burkholderia ambifaria, Viscum album ou contre le virus de la grippe. Dans le futur, pour mieux appréhender les mécanismes d’interactions sucres/protéines, il serait intéressant de pouvoir suivre en temps réel ces interactions en utilisant des systèmes de détection sans marquage tel que, par exemple, la résonance plasmonique de surface. Aussi, le dernier chapitre donne les prémices d’une adaptation de la méthode DDI sur glycoarray sur surface d’or.

Pseudomonas aeruginosa (PA) is one of the predominant bacterium encountered in nosocomial infections. PA infections often lead to chronic inflammation and eventually to death despite aggressive antibiotic therapy. A promising approach is to inhibit the virulence factors of PA such as PA-IL, PA-IIL, FliD (lectins). Therefore, there is a great interest for studying carbohydrate/lectin interactions in order to design new treatments. The goal of this work is the research for inhibitory molecules (glycoclusters ) of these lectins involved in the…

Advisors/Committee Members: Souteyrand, Eliane (thesis director).

Subjects/Keywords: Glycobiologie; Interaction glycocluster/lectine; Glycoarray; Chimie de surface; Immobilisation dirigée par l’ADN (DDI); Glycobiology; Glycocluster/lectin interaction; Glycoarray; Surface chemistry; DNA directed immobilization (DDI)

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Goudot, A. (2013). Développement d'une plateforme de criblage pour la recherche de nouvelles molécules anti-infectieuses : applications à Pseudomonas aeruginosa. : Glycoarray technology development for new anti-infective molecules discovering : applications to Pseudomonas aeruginosa. (Doctoral Dissertation). Ecully, Ecole centrale de Lyon. Retrieved from http://www.theses.fr/2013ECDL0023

Chicago Manual of Style (16^th Edition):

Goudot, Alice. “Développement d'une plateforme de criblage pour la recherche de nouvelles molécules anti-infectieuses : applications à Pseudomonas aeruginosa. : Glycoarray technology development for new anti-infective molecules discovering : applications to Pseudomonas aeruginosa.” 2013. Doctoral Dissertation, Ecully, Ecole centrale de Lyon. Accessed April 11, 2021. http://www.theses.fr/2013ECDL0023.

MLA Handbook (7^th Edition):

Goudot, Alice. “Développement d'une plateforme de criblage pour la recherche de nouvelles molécules anti-infectieuses : applications à Pseudomonas aeruginosa. : Glycoarray technology development for new anti-infective molecules discovering : applications to Pseudomonas aeruginosa.” 2013. Web. 11 Apr 2021.

Vancouver:

Goudot A. Développement d'une plateforme de criblage pour la recherche de nouvelles molécules anti-infectieuses : applications à Pseudomonas aeruginosa. : Glycoarray technology development for new anti-infective molecules discovering : applications to Pseudomonas aeruginosa. [Internet] [Doctoral dissertation]. Ecully, Ecole centrale de Lyon; 2013. [cited 2021 Apr 11]. Available from: http://www.theses.fr/2013ECDL0023.

Council of Science Editors:

Goudot A. Développement d'une plateforme de criblage pour la recherche de nouvelles molécules anti-infectieuses : applications à Pseudomonas aeruginosa. : Glycoarray technology development for new anti-infective molecules discovering : applications to Pseudomonas aeruginosa. [Doctoral Dissertation]. Ecully, Ecole centrale de Lyon; 2013. Available from: http://www.theses.fr/2013ECDL0023

University of Melbourne

6. Hameed, Pathima Nusrath. In silico methods for drug repositioning and drug-drug interaction prediction.

Degree: 2018, University of Melbourne

URL: http://hdl.handle.net/11343/219484

► Drug repositioning and drug-drug interaction (DDI) prediction are two fundamental applications having a large impact on drug development and clinical care. Drug repositioning aims to… (more)

▼ Drug repositioning and drug-drug interaction (DDI) prediction are two fundamental applications having a large impact on drug development and clinical care. Drug repositioning aims to identify new uses for existing drugs. Moreover, understanding harmful DDIs is essential to enhance the effects of clinical care. Exploring both therapeutic uses and adverse effects of drugs or a pair of drugs have significant benefits in pharmacology. The use of computational methods to support drug repositioning and DDI prediction enable improvements in the speed of drug development compared to in vivo and in vitro methods. This thesis investigates the consequences of employing a representative training sample in achieving better performance for DDI classification. The Positive-Unlabeled Learning method introduced in this thesis aims to employ representative positives as well as reliable negatives to train the binary classifier for inferring potential DDIs. Moreover, it explores the importance of a finer-grained similarity metric to represent the pairwise drug similarities. Drug repositioning can be approached by new indication detection. In this study, Anatomical Therapeutic Chemical (ATC) classification is used as the primary source to determine the indications/therapeutic uses of drugs for drug repositioning. This thesis presents a two-tiered clustering approach for obtaining pairwise drug similarity and heterogeneous drug data integration which is employed for large-scale drug repositioning. Moreover, this thesis demonstrates subnetwork identification as a suitable approach for new indication detection for existing drugs. Subnetwork identification method identifies a subgraph from a large drug similarity network, connecting a set of given drugs known as ‘terminals’. In this study, the ‘terminals’ are selected according to the ATC classification system; hence meaningful subnetworks are identified. The proposed subnetwork identification method is employed to infer drug repositioning candidates for cardiovascular diseases and diseases related to the nervous system. New target detection for existing drugs is also beneficial for drug repositioning. This thesis proposes a useful computational method for target clustering which is extended to identify new drug-target relationships. It demonstrates the significance of integrating dimensionality reduction and outlier detection to overcome the limitations arising from the incomplete drug-target interaction data. The clinical significance and literature-based evidence illustrate the relevance of the proposed methods. The proposed methods can be employed in other similar applications where applicable.

Subjects/Keywords: drug repurposing; biomedical informatics; DDI prediction; drug-target prediction; heterogeneous data integration; cluster evaluation

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hameed, P. N. (2018). In silico methods for drug repositioning and drug-drug interaction prediction. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/219484

Chicago Manual of Style (16^th Edition):

Hameed, Pathima Nusrath. “In silico methods for drug repositioning and drug-drug interaction prediction.” 2018. Doctoral Dissertation, University of Melbourne. Accessed April 11, 2021. http://hdl.handle.net/11343/219484.

MLA Handbook (7^th Edition):

Hameed, Pathima Nusrath. “In silico methods for drug repositioning and drug-drug interaction prediction.” 2018. Web. 11 Apr 2021.

Vancouver:

Hameed PN. In silico methods for drug repositioning and drug-drug interaction prediction. [Internet] [Doctoral dissertation]. University of Melbourne; 2018. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/11343/219484.

Council of Science Editors:

Hameed PN. In silico methods for drug repositioning and drug-drug interaction prediction. [Doctoral Dissertation]. University of Melbourne; 2018. Available from: http://hdl.handle.net/11343/219484

University of Otago

7. Lee, Au-Chen. Dipolar Bose-Einstein Condensate with a Vortex .

Degree: University of Otago

URL: http://hdl.handle.net/10523/9254

► We theoretically consider the properties of a dipolar Bose-Einstein condensate with a vortex. Our theory includes the influence of the leading order quantum fluctuation corrections… (more)

Subjects/Keywords: Bose-einstein condensates; BEC; nonlinear; condensate; Gross-Pitaevskii; nonlinear Schrödinger equation; vortices; Collective excitations; vortex self-bound droplets; dipolar BEC; dipolar quantum; quantum fluctuations; Bogoliubov-de Gennes; instability; quadrupolar modes; dynamical stability; dipole interaction; density approximation; dipolar Bose-Einstein condensate; quasi-particle excitations; vortex; Hankel Transformation; Bessel function; cosine transformation; Cylindrical; BdG; Bogoliubov-de Gennes Equation; numerical calculations; DDI; dipole-dipole interactions; phonon dispersion; dynamical instability; eigenvalue problem; eigenvector; imaginary time evolution; laplacian operator; GPE; Gross–Pitaevskii equation; zero-norm; Kohn modes; Bessel grid; DDIs; numerical techniques; dipolar; dipolar BECs; LHY term; local density treatment; vortex stationary states; Kelvin wave (helical) excitations; stabilized from collapse; quasi-particle; leading order quantum fluctuation correction; lanthanides dysprosium; dysprosium; Dy; s-wave interaction; many-body physics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Lee, A. (n.d.). Dipolar Bose-Einstein Condensate with a Vortex . (Masters Thesis). University of Otago. Retrieved from http://hdl.handle.net/10523/9254

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Chicago Manual of Style (16^th Edition):

Lee, Au-Chen. “Dipolar Bose-Einstein Condensate with a Vortex .” Masters Thesis, University of Otago. Accessed April 11, 2021. http://hdl.handle.net/10523/9254.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

MLA Handbook (7^th Edition):

Lee, Au-Chen. “Dipolar Bose-Einstein Condensate with a Vortex .” Web. 11 Apr 2021.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Lee A. Dipolar Bose-Einstein Condensate with a Vortex . [Internet] [Masters thesis]. University of Otago; [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10523/9254.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Council of Science Editors:

Lee A. Dipolar Bose-Einstein Condensate with a Vortex . [Masters Thesis]. University of Otago; Available from: http://hdl.handle.net/10523/9254

Note: this citation may be lacking information needed for this citation format:
No year of publication.

University of Cincinnati

8. Moorthy, Ganesh. Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment.

Degree: PhD, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics, 2015, University of Cincinnati

URL: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439296033

► Dysregulation of PI3K/Akt/mTOR pathway has been implicated in tumorigenesis and malignancy in numerous solid tumors. Everolimus is a potent allosteric inhibitor of mTORC1, and has… (more)

▼ Dysregulation of PI3K/Akt/mTOR pathway has been implicated in tumorigenesis and malignancy in numerous solid tumors. Everolimus is a potent allosteric inhibitor of mTORC1, and has been approved for the treatment of number of cancers including renal and breast cancer. BEZ235, a dual PI3K/ mTOR inhibitor, in combination with everolimus has shown promising in vitro and preclinical evidence for synergistic activity against solid tumors. This led to an investigator initiated Phase 1b clinical trial to determine the safety, pharmacokinetics and pharmacodynamics of the combination of BEZ235 with everolimus in subjects with advanced solid tumors. The combination of BEZ235 and everolimus has the potential for significant pharmacokinetic drug-drug interaction (DDI), given the prominent role of cytochrome P450 3A4 (CYP3A4) in the metabolism of everolimus. Thus, the integral aspect of the dissertation was to evaluate the pharmacokinetics of the two agents, investigate DDI and to conduct correlative studies to assess the mechanism(s) that may underlie this DDI. We describe here, 1) first report of clinical pharmacokinetics of BEZ235 at doses ranging from 200 to 800 mg/day with everolimus at 2.5 mg/day, and investigation of DDI, 2) correlative studies to delineate the mechanism of this interaction, 3) mechanistic physiologically based pharmacokinetic modeling (PBPK) to understand the impact of physiological and drug specific parameters on DDI.Phase I dose escalation consisted of 28-day study treatment cycles with BEZ235 doses of 200, 400 and 800 mg/day with everolimus at 2.5 mg/day. Nineteen subjects were enrolled in the study and blood samples were collected on days 1 and 28. We delineated the pharmacokinetics of BEZ23 on day 1 and day 28, which was linear and dose proportional in the dose range tested. Everolimus pharmacokinetics was evaluated on day 1 and day 28, there was a significant increase in everolimus blood Cmax and AUC0-24 from day 1 to day 28. Everolimus clearance (CL/F) decreased from 24.76±2.91 L/h on day 1 to 13.41±2.31 L/hr on day 28. Population based and non-compartmental approaches showed that there was a 1.7 fold increase in everolimus when dosed with BEZ235. In correlative in vitro studies, BEZ235 was observed to be a time-dependent inhibitor (TDI) of CYP3A4. In primary human hepatocytes, BEZ235 had a potential to induce CYP3A4 based on mRNA levels however, there was no corresponding increase in CYP3A4 activity. A PBPK model was developed using mechanistic static and dynamic model to study the interaction. Prediction based on both the models were close to the observed interaction. PBPK simulations indicated a 5-fold reduction in gut CYP3A4 activity in presence of BEZ235, leading to a significant decrease in everolimus gut metabolism. Thus, an increase in everolimus Fg, fraction escaping gut metabolism, when co-administered with BEZ235 might play a role in the observed interaction. Overall, Phase I study provide insights into the pharmacokinetics and suggest that the systemic exposure of BEZ235 and everolimus… Advisors/Committee Members: Desai, Pankaj (Committee Chair).

Subjects/Keywords: Pharmaceuticals; pharmacokinetics; Phase I; PBPK; DDI; BEZ235; Everolimus

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Moorthy, G. (2015). Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439296033

Chicago Manual of Style (16^th Edition):

Moorthy, Ganesh. “Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment.” 2015. Doctoral Dissertation, University of Cincinnati. Accessed April 11, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439296033.

MLA Handbook (7^th Edition):

Moorthy, Ganesh. “Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment.” 2015. Web. 11 Apr 2021.

Vancouver:

Moorthy G. Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment. [Internet] [Doctoral dissertation]. University of Cincinnati; 2015. [cited 2021 Apr 11]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439296033.

Council of Science Editors:

Moorthy G. Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment. [Doctoral Dissertation]. University of Cincinnati; 2015. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439296033

Swedish University of Agricultural Sciences

9. Sun, Ren. Studies of enzymes in mitochondrial DNA precursor synthesis.

Degree: 2013, Swedish University of Agricultural Sciences

URL: http://pub.epsilon.slu.se/10780/

► As important enzymes in mitochondrial nucleotide salvage pathway, thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) are expressed constitutively in almost all cells. These two… (more)

▼ As important enzymes in mitochondrial nucleotide salvage pathway, thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) are expressed constitutively in almost all cells. These two enzymes catalyze the initial rate-limiting phosphorylation of pyrimidine and purine deoxynucleosides, respectively, providing DNA precursors for mitochondrial DNA (mtDNA) replication. Inherited genetic defects in TK2 have been associated with infantile myopathic form of mtDNA depletion syndrome (MDS). In study I, two mutations, R225W and a novel T230A, in TK2 are identified as a new genetic cause of adult-onset autosomal recessive progressive external ophthalmoplegia (arPEO) and the kinetic and structural effects of the two mutations on enzyme function have been characterized. Nucleoside analogs are widely used in anti-viral and anti-cancer chemotherapy, but they can cause severe side-effect such as mtDNA depletion. In study II, the potential mechanism underlying pyrimidine nucleoside analogs-associated mitochondrial toxicities was investigated, and showed that thymidine analogs had opposite effects on dThd and dCyd phosphorylation and thus can inhibit dThd salvage, leading to imbalanced dTTP and dCTP pools. It was found that the mechanism is most likely due to that TK2 normally exists in an inactive form with bound dTTP. The redox regulation of TK2 and dGK was studied in study III and IV. The activity of both enzymes was sensitive to the cellular redox status. Under oxidative stress, both TK2 and dGK can be reversibly S-glutathionylated by GSSG. The modification of the conserved Cys189 in TK2 was responsible for a partial inactivation and selective degradation of TK2 in mitochondria, most likely via the AAA⁺ Lon protease. The oxidative effect of nucleoside analogs was also evaluated. Treatment with 3’-azido- 2’,3’-dideoxythymidine (AZT) and 2’,3’-dideoxyinosine (ddI) led to degradation of mitochondrial TK2 and dGK, whereas uridine and guanosine supplementations to AZT respective ddI treatments prevented both proteins from degradation.

Subjects/Keywords: enzymes; thymidine; kinases; mitochondria; dna; Thymidine kinase 2; Deoxyguanosine kinase; Mitochondrial DNA; Progressive external ophthalmoplegia; Nucleoside analogs; AZT (3’-azido-2’,3’- dideoxythymidine); ddI (2’,3’-dideoxyinosine); S-glutathionylation

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Sun, R. (2013). Studies of enzymes in mitochondrial DNA precursor synthesis. (Doctoral Dissertation). Swedish University of Agricultural Sciences. Retrieved from http://pub.epsilon.slu.se/10780/

Chicago Manual of Style (16^th Edition):

Sun, Ren. “Studies of enzymes in mitochondrial DNA precursor synthesis.” 2013. Doctoral Dissertation, Swedish University of Agricultural Sciences. Accessed April 11, 2021. http://pub.epsilon.slu.se/10780/.

MLA Handbook (7^th Edition):

Sun, Ren. “Studies of enzymes in mitochondrial DNA precursor synthesis.” 2013. Web. 11 Apr 2021.

Vancouver:

Sun R. Studies of enzymes in mitochondrial DNA precursor synthesis. [Internet] [Doctoral dissertation]. Swedish University of Agricultural Sciences; 2013. [cited 2021 Apr 11]. Available from: http://pub.epsilon.slu.se/10780/.

Council of Science Editors:

Sun R. Studies of enzymes in mitochondrial DNA precursor synthesis. [Doctoral Dissertation]. Swedish University of Agricultural Sciences; 2013. Available from: http://pub.epsilon.slu.se/10780/

Open Access Theses and Dissertations