subject:(efflux transporters)

Universidade do Rio Grande do Sul

1. Zimmermann, Estevan Sonego. Modelagem farmacocinética populacional na avaliação do papel da glicoproteína-P na penetração tecidual de fluoroquinolonas.

Degree: 2015, Universidade do Rio Grande do Sul

URL: http://hdl.handle.net/10183/163764

► Objetivos: O objetivo deste trabalho foi desenvolver modelo farmacocinético (popPK) populacional para descrever simultaneamente as concentrações das fluoroquinolonas (levofloxacino – LEV e ciprofloxacino – CIP)… (more)

▼ Objetivos: O objetivo deste trabalho foi desenvolver modelo farmacocinético (popPK) populacional para descrever simultaneamente as concentrações das fluoroquinolonas (levofloxacino – LEV e ciprofloxacino – CIP) no plasma, pulmão e próstata na presença e ausência do inibidor da P-gp tariquidar (TAR) visando determinar a contribuição desse transportador de efluxo na distribuição tecidual desses antimicrobianos. Método: Para alcançar este objetivo as seguintes etapas foram realizadas: i) foi validado o método analítico de HPLC-fluorescência para quantificação de CIP em amostras de plasma e microdialisado; ii) foram estabelecidas as condições para microdiálise para o CIP e as taxas de recuperação in vitro, por diálise e retrodiálise, e em tecido pulmonar e prostático in vivo por retrodiálise; iii) foi avaliada a farmacocinética do LEV após administração a ratos Wistar via i.v. bolus e por nebulização intratraqueal na dose de 7mg/kg na ausência e após administração prévia de TAR (15 mg/Kg i.v.); iv) foi desenvolvido um modelo popPK para prever as concentrações do LEV simultaneamente no plasma, pulmão e próstata após administração intravenosa e intratraqueal na presença e ausência do TAR; v) foi desenvolvido o modelo popPK para descrever as concentrações de CIP simultaneamente no plasma, pulmão e próstata após administração a ratos Wistar da dose de 7 mg/kg i.v. bolus na presença e ausência de TAR (15 mg/kg i.v.); vi) Para ambos os fármacos os dados foram avaliados por análise não-compartimental e modelados por modelo de quatro compartimentos modificado, com ajuda do software NONMEN®. Resultados e Conclusões. i) Método analítico foi desenvolvido e validado com sucesso para quantificação de CIP em HPLC/fluorescência mostrando-se linear na faixa de 10–2000 ng/mL em plasma e 5–1000 ng/mL em microdialisado com coeficientes de determinação (r2) superiores a 0,99. Os valores obtidos de erro padrão relativo para ensaios de precisão intra e inter-dia foram entre 8,8 e 6,0 %, para microdialisado entre 11,1 e 7,4 % para plasma, respectivamente. Os valores de exatidão foram 86,1% entre 114.3% para microdialisado e 85,6% entre 108,2% para plasma; ii) A avaliação do CIP por microdiálise mostrou recuperação concentração independente (0,25 - 1,5 μg/mL). Além disso, não houve diferença entre as recuperações obtidas por diálise e retrodiálise para o mesmo fluxo. No fluxo selecionado para os experimentos (1,5 μL/min) as recuperações médias por diálise e retrodiálise foram 23,0 ± 2,8% e 22,8 ± 1,6 %, respectivamente. A recuperação relativa das sondas in vivo foi de 11,3 ± 1,9 e 13,1 ± 2,7 % para pulmão e próstata, respectivamente; iii) A análise dos perfis plasmáticos e teciduais LEV após dose intravenosa do grupo controle (sem TAR) mostrou boa penetração tecidual na próstata (ƒT = 0,68) e no pulmão (ƒT = 0,69). Para a mesma via de administração, o grupo TAR mostrou uma penetração praticamente inalterada para o pulmão (ƒT = 0,81) e um aumento de mais de 2 vezes na penetração prostática (ƒT= 1,64). Na dose intratraqueal houve um aumento… Advisors/Committee Members: Dalla Costa, Teresa Cristina Tavares.

Subjects/Keywords: Fluoroquinolones; Fluoroquinolonas; Farmacocinética; Pharmacokinetic; Efflux transporters; PopPK modeling; Microdialysis

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APA (6^th Edition):

Zimmermann, E. S. (2015). Modelagem farmacocinética populacional na avaliação do papel da glicoproteína-P na penetração tecidual de fluoroquinolonas. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/163764

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):

Zimmermann, Estevan Sonego. “Modelagem farmacocinética populacional na avaliação do papel da glicoproteína-P na penetração tecidual de fluoroquinolonas.” 2015. Thesis, Universidade do Rio Grande do Sul. Accessed March 07, 2021. http://hdl.handle.net/10183/163764.

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

MLA Handbook (7^th Edition):

Zimmermann, Estevan Sonego. “Modelagem farmacocinética populacional na avaliação do papel da glicoproteína-P na penetração tecidual de fluoroquinolonas.” 2015. Web. 07 Mar 2021.

Vancouver:

Zimmermann ES. Modelagem farmacocinética populacional na avaliação do papel da glicoproteína-P na penetração tecidual de fluoroquinolonas. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2015. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10183/163764.

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

Council of Science Editors:

Zimmermann ES. Modelagem farmacocinética populacional na avaliação do papel da glicoproteína-P na penetração tecidual de fluoroquinolonas. [Thesis]. Universidade do Rio Grande do Sul; 2015. Available from: http://hdl.handle.net/10183/163764

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

University of Arizona

2. Kim, Eun-Hae. Maintaining Copper Homeostasis - Molecular Studies on Bacterial Copper Transporters .

Degree: 2011, University of Arizona

URL: http://hdl.handle.net/10150/205232

► Bacteria have evolved sophisticated cellular transport mechanisms to maintain metal homeostasis to not only utilize metals as important cofactors but also to evade the toxicity… (more)

Subjects/Keywords: HME; metal; RND; transporters; Soil, Water & Environmental Science; copper; efflux

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

APA (6^th Edition):

Kim, E. (2011). Maintaining Copper Homeostasis - Molecular Studies on Bacterial Copper Transporters . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/205232

Chicago Manual of Style (16^th Edition):

Kim, Eun-Hae. “Maintaining Copper Homeostasis - Molecular Studies on Bacterial Copper Transporters .” 2011. Doctoral Dissertation, University of Arizona. Accessed March 07, 2021. http://hdl.handle.net/10150/205232.

MLA Handbook (7^th Edition):

Kim, Eun-Hae. “Maintaining Copper Homeostasis - Molecular Studies on Bacterial Copper Transporters .” 2011. Web. 07 Mar 2021.

Vancouver:

Kim E. Maintaining Copper Homeostasis - Molecular Studies on Bacterial Copper Transporters . [Internet] [Doctoral dissertation]. University of Arizona; 2011. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10150/205232.

Council of Science Editors:

Kim E. Maintaining Copper Homeostasis - Molecular Studies on Bacterial Copper Transporters . [Doctoral Dissertation]. University of Arizona; 2011. Available from: http://hdl.handle.net/10150/205232

University of Adelaide

3. Pederick, Victoria Grace. Characterisation of the ATP-binding cassette transporters of Pseudomonas aeruginosa.

Degree: 2015, University of Adelaide

URL: http://hdl.handle.net/2440/106301

► Pseudomonas aeruginosa is a ubiquitous, Gram-negative, rod-shaped, environmental bacterium. However, it is also a clinically significant, opportunistic human pathogen, responsible for life-threatening infections in immunocompromised… (more)

▼ Pseudomonas aeruginosa is a ubiquitous, Gram-negative, rod-shaped, environmental bacterium. However, it is also a clinically significant, opportunistic human pathogen, responsible for life-threatening infections in immunocompromised persons, including those with cancer and significant burn wounds. Furthermore, P. aeruginosa infections are the primary cause of morbidity and mortality in individuals with the genetic disease cystic fibrosis. The success of P. aeruginosa as both an environmental organism and a human pathogen can be attributed to its 6.3 Mbp genome, which encodes an array of mechanisms that enable adaptation, persistence and propagation in diverse environments. Membrane transporters are critical to the ability of P. aeruginosa to adapt and respond to its environment. Of these proteins, the ATP-binding cassette (ABC) transporters hold a prominent role in cellular processes, facilitating the active translocation of molecules across the inner membrane. The conserved structural organisation of ABC transporters has enabled their classification based upon the vector of transport, as either efflux or import transporters. Bioinformatic analyses reveal that P. aeruginosa PAO1 is predicted to encode 289 proteins associated with ABC transporter functionality, with a subset shown to contribute to in vivo virulence. This study presents the phenotypic characterisation of five putative ABC export proteins in P. aeruginosa PAO1, assessing their contribution to antibiotic efflux. Deletion mutants of each identified ABC exporter were assessed for changes in their antibiotic resistance profile. Transcriptional analysis of the ABC transporter genes in response to antibiotic treatment was also performed to detect drug-stimulated expression. These analyses revealed the PA0860, PA1113, PA1876, PA3228 and PA5231 ABC efflux proteins to have a negligible contribution to antibiotic resistance, with bioinformatic analyses subsequently utilized to propose alternative roles. ABC importers, also known as ABC permeases, typically feature one, but sometimes multiple, solute-binding protein (SBP) component(s) that deliver the cargo molecule to the ABC transporter for cytoplasmic translocation. ABC permeases are central to the uptake of many essential nutrients in prokaryotes, including transition metal ions. Herein, this study characterises the acquisition and role of two crucial transition metal ions, molybdenum and zinc, in P. aeruginosa. Acquisition of either metal ion was shown to occur primarily via ABC permeases, molybdenum via ModABC, and zinc via ZnuABC. Deletion of the modA SBP gene abrogated molybdenum accumulation in P. aeruginosa and abolished the capacity for anaerobic growth or nitrate reduction. Unexpectedly, conditions that permitted nitrate reduction were shown to inhibit biofilm formation and alter membrane fatty acid composition. By contrast, although deletion of the zinc-specific SBP gene, znuA, reduced cellular zinc accumulation, the mutant strain did not exhibit a phenotype corresponding with zinc depletion.… Advisors/Committee Members: McDevitt, Christopher (advisor), Paton, James Cleland (advisor), School of Molecular and Biomedical Science (school).

Subjects/Keywords: pseudomonas aeruginosa; ABC transporters; zinc; molybdenum; metal ion import; drug efflux

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

APA (6^th Edition):

Pederick, V. G. (2015). Characterisation of the ATP-binding cassette transporters of Pseudomonas aeruginosa. (Thesis). University of Adelaide. Retrieved from http://hdl.handle.net/2440/106301

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):

Pederick, Victoria Grace. “Characterisation of the ATP-binding cassette transporters of Pseudomonas aeruginosa.” 2015. Thesis, University of Adelaide. Accessed March 07, 2021. http://hdl.handle.net/2440/106301.

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

MLA Handbook (7^th Edition):

Pederick, Victoria Grace. “Characterisation of the ATP-binding cassette transporters of Pseudomonas aeruginosa.” 2015. Web. 07 Mar 2021.

Vancouver:

Pederick VG. Characterisation of the ATP-binding cassette transporters of Pseudomonas aeruginosa. [Internet] [Thesis]. University of Adelaide; 2015. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/2440/106301.

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

Council of Science Editors:

Pederick VG. Characterisation of the ATP-binding cassette transporters of Pseudomonas aeruginosa. [Thesis]. University of Adelaide; 2015. Available from: http://hdl.handle.net/2440/106301

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

University of Minnesota

4. Laramy, Janice. Permeability, binding and distributional kinetics of Ponatinib, a multi-kinase inhibitor: implications for the treatment of brain tumors.

Degree: PhD, Pharmaceutics, 2018, University of Minnesota

URL: http://hdl.handle.net/11299/213085

► Glioblastoma (GBM) is the most common malignant brain tumor and one of the unmet medical needs. Among over 1,000 GBM clinical trials testing molecularly-targeted agents,… (more)

Subjects/Keywords: Blood-brain barrier; Efflux transporters; Glioblastoma; Tyrosine kinase inhibitor

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

APA (6^th Edition):

Laramy, J. (2018). Permeability, binding and distributional kinetics of Ponatinib, a multi-kinase inhibitor: implications for the treatment of brain tumors. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/213085

Chicago Manual of Style (16^th Edition):

Laramy, Janice. “Permeability, binding and distributional kinetics of Ponatinib, a multi-kinase inhibitor: implications for the treatment of brain tumors.” 2018. Doctoral Dissertation, University of Minnesota. Accessed March 07, 2021. http://hdl.handle.net/11299/213085.

MLA Handbook (7^th Edition):

Laramy, Janice. “Permeability, binding and distributional kinetics of Ponatinib, a multi-kinase inhibitor: implications for the treatment of brain tumors.” 2018. Web. 07 Mar 2021.

Vancouver:

Laramy J. Permeability, binding and distributional kinetics of Ponatinib, a multi-kinase inhibitor: implications for the treatment of brain tumors. [Internet] [Doctoral dissertation]. University of Minnesota; 2018. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/11299/213085.

Council of Science Editors:

Laramy J. Permeability, binding and distributional kinetics of Ponatinib, a multi-kinase inhibitor: implications for the treatment of brain tumors. [Doctoral Dissertation]. University of Minnesota; 2018. Available from: http://hdl.handle.net/11299/213085

University of California – Berkeley

5. Boyarskiy, Sergey. Small molecule membrane transporters for enhanced microbial production of biochemicals.

Degree: Bioengineering, 2015, University of California – Berkeley

URL: http://www.escholarship.org/uc/item/2w31g4zc

► Metabolic engineering has been applied to a variety of microbial hosts to enhance production of compounds spanning from biofuels to pharmaceuticals. In all cases metabolic… (more)

▼ Metabolic engineering has been applied to a variety of microbial hosts to enhance production of compounds spanning from biofuels to pharmaceuticals. In all cases metabolic engineering requires the identification and optimization of the production pathway; however, engineering of optimal host strains capable of reliable production is multi-layered and complex. Strain engineering beyond the primary conversion pathway can lead to improved production levels, more robust strains, and better compatibility with downstream recovery methods. A common area where this facet of strain engineering becomes important is in alleviating the encumbrance on the cell caused by high product concentrations. In particular, these concerns are most relevant where productivity has to be maximized to achieve economic value, such as in commodity chemical and biofuel production. Many of the compounds valuable on an industrial scale are solvent-like hydrocarbons, where the accumulation of the compound is toxic to the cell. Furthermore separation of the somewhat hydrophobic compound becomes difficult as the large scale of the product formation leads to dissolved cell contaminants in the final product.One potential engineering platform – efflux pumps – addresses many of the difficulties that come about from increased product yields. Engineered efflux transporters can secrete the product from the host thereby eliminating any potentially unwanted interactions between the product and the entirety of cellular machinery. Furthermore, secretion serves as a preliminary purification step for those compounds that are easily miscible with the rest of the cellular environment. This work discusses advances in the use of native and engineered efflux transporters to increase biochemical productivity. To this end, our first approach was to utilize directed evolution to mutate the native Escherichia coli efflux transporter AcrB to secrete the biofuel butanol. While AcrB’s native function is mainly in stabilizing E. coli tolerance to bile salts and antibiotics, we were able to alter its specificity towards n-butanol and other short, straight-chain alcohols. We managed to increase tolerance of the cells expressing these mutant pumps to butanol as well as increase titers of butanol when the production pathways were added into the strains. In addition to demonstrating that directed evolution approaches can be used to enhance secretion of toxic products from the cell, we developed a continuum kinetics model of transporter activity and molecular diffusion of small molecules across the membrane. An interesting conclusion of this model shows that efflux transporters are likely to have the most benefit in the secretion of more hydrophilic molecules. However, when the model is expanded to include phase formation and separation of highly hydrophobic molecules, a new function for transporters is found. Transporters acting on very hydrophobic molecules are theoretically capable of creating a gradient strong enough to drive phase formation outside of the cell while keeping…

Subjects/Keywords: Biomedical engineering; Microbiology; Chemical engineering; Biofuels; Efflux transporters; Membrane transport; Microbial tolerance

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

APA (6^th Edition):

Boyarskiy, S. (2015). Small molecule membrane transporters for enhanced microbial production of biochemicals. (Thesis). University of California – Berkeley. Retrieved from http://www.escholarship.org/uc/item/2w31g4zc

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):

Boyarskiy, Sergey. “Small molecule membrane transporters for enhanced microbial production of biochemicals.” 2015. Thesis, University of California – Berkeley. Accessed March 07, 2021. http://www.escholarship.org/uc/item/2w31g4zc.

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

MLA Handbook (7^th Edition):

Boyarskiy, Sergey. “Small molecule membrane transporters for enhanced microbial production of biochemicals.” 2015. Web. 07 Mar 2021.

Vancouver:

Boyarskiy S. Small molecule membrane transporters for enhanced microbial production of biochemicals. [Internet] [Thesis]. University of California – Berkeley; 2015. [cited 2021 Mar 07]. Available from: http://www.escholarship.org/uc/item/2w31g4zc.

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

Council of Science Editors:

Boyarskiy S. Small molecule membrane transporters for enhanced microbial production of biochemicals. [Thesis]. University of California – Berkeley; 2015. Available from: http://www.escholarship.org/uc/item/2w31g4zc

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

University of Manchester

6. Shajiei, Arezoo. INCREASED THERAPEUTIC INDEX OF TYROSINE KINASE INHIBITORS IN CML THROUGH MEMBRANE TRANSPORTER UPTAKE.

Degree: 2017, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309621

► Chronic myeloid leukaemia (CML) is a hematopoietic stem cell disease, distinguished by the BCR-ABL gene and the presence of the Philadelphia chromosome. Recent studies have… (more)

▼ Chronic myeloid leukaemia (CML) is a hematopoietic stem cell disease, distinguished by the BCR-ABL gene and the presence of the Philadelphia chromosome. Recent studies have revealed that CML resistance is due to up regulation of the membrane and drug transporters ABCB1 and ABCG2, which have a critical role in drug resistance. Indeed, there is strong evidence suggesting drug transport occurs mainly via proteinaceous carriers. In this regards, the MayBridge Rule of 3 Fragment Library (May Ro3) is a relatively small collection of chemical moieties that are pharmacophore rich and â€˜metabolite-likeâ€™. As a result, in the current project we demonstrate the application of 'binary weapons' which are small non-toxic molecular agents with high affinity to both transporters and imatinib. The interaction between the binary weapon and imatinib enhances the anti-cancer impact of imatinib. In this research study, the first 500 fragments from the Maybridge Fragment (MBF) library was screened to find suitable candidates for enhancing the imatinib effect on K562 cell line while the MBFs alone possessed no toxic effect. Firstly the screenings were performed by pooling fragments, in which we tested the K562 cell enhanced toxicity of imatinib plus MBFs via MTT assays and then those selected pools were analysed in single MBF screenings. Then titration assays of those selected single hits were performed to find the most effective concentration for selected hits. Finally, the selected single hits were used in qPCR to check the effect on expression of candidate membrane associated transporters that were identified from literature review. Moreover, in all experiments SH-SY5Y cells and the drug cisplatin were employed as controls for K562 and imatinib. In pooled screens for K562 and imatinib, 40 fragments were selected and these pools were further investigated using single MBF screenings and 6 of the 40 MBFs showed the desired effect. Following titration experiments, 2 MBFs were shown to carry the least toxicity even in the highest concentrations, so they were selected as candidates for investigation of the impact on the expression of transporters genes. The expression of transporter mRNAs was investigated and showed some significant dys-regulation of influx or efflux transporters. Compared to the control group, when K562 cells were treated with MBFs (161 or 247), all transporters, efflux and influx, showed downregulation. However, treatment with imatinib and MBF No. 161 for 1 hour showed downregulation for ABCB10, BCR-ABL and SLCO1A2SLCO1A2(P-value = 0.001). However, the expression for other transporters were not dysregulated (no upregulation no downregulation) (P value=0.001), showing the same expression with the control group. Moreover, treatment of K562 cells with imatinib and MBF hit No. 247, all influx and efflux transporters were downregulated significantly. Lastly, the BCR-ABL expression in all different conditions showed downregulation. In this research programme, K562 served as target cells and as a model of CML while SH-SHY5Y were… Advisors/Committee Members: KELL, DOUGLAS DB, VERMA, MALKHEY M, Day, Philip, Kell, Douglas, Verma, Malkhey.

Subjects/Keywords: Chronic myeloid leukaemia (CML); Maybridge Fragment (MBF); imatinib; influx or efflux transporters

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

APA (6^th Edition):

Shajiei, A. (2017). INCREASED THERAPEUTIC INDEX OF TYROSINE KINASE INHIBITORS IN CML THROUGH MEMBRANE TRANSPORTER UPTAKE. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309621

Chicago Manual of Style (16^th Edition):

Shajiei, Arezoo. “INCREASED THERAPEUTIC INDEX OF TYROSINE KINASE INHIBITORS IN CML THROUGH MEMBRANE TRANSPORTER UPTAKE.” 2017. Doctoral Dissertation, University of Manchester. Accessed March 07, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309621.

MLA Handbook (7^th Edition):

Shajiei, Arezoo. “INCREASED THERAPEUTIC INDEX OF TYROSINE KINASE INHIBITORS IN CML THROUGH MEMBRANE TRANSPORTER UPTAKE.” 2017. Web. 07 Mar 2021.

Vancouver:

Shajiei A. INCREASED THERAPEUTIC INDEX OF TYROSINE KINASE INHIBITORS IN CML THROUGH MEMBRANE TRANSPORTER UPTAKE. [Internet] [Doctoral dissertation]. University of Manchester; 2017. [cited 2021 Mar 07]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309621.

Council of Science Editors:

Shajiei A. INCREASED THERAPEUTIC INDEX OF TYROSINE KINASE INHIBITORS IN CML THROUGH MEMBRANE TRANSPORTER UPTAKE. [Doctoral Dissertation]. University of Manchester; 2017. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309621

7. Lê, Minh. L'apport de l'évaluation pharmacocinétique dans le choix des antirétroviraux (nature et dose) chez la personne vivant avec le VIH : Contribution of pharmacokinetic assessment in the selection of antiretroviral therapy (type and dose) in HIV-infected patients.

Degree: Docteur es, Epidémiologie et sciences de l'information biomédicale. Epidémiologie clinique, 2019, Sorbonne Paris Cité

URL: http://www.theses.fr/2019USPCC020

►

En dépit des récentes avancées thérapeutiques, l’infection par le VIH pour être contrôlée nécessite le maintien à vie d’un traitement antirétroviral (ARV). De ce fait,… (more)

▼

En dépit des récentes avancées thérapeutiques, l’infection par le VIH pour être contrôlée nécessite le maintien à vie d’un traitement antirétroviral (ARV). De ce fait, des stratégies d’allègements destinées à réduire la « charge chimique » sont proposées afin de maintenir l’efficacité antivirale tout en améliorant le profil de tolérance. Les compartiments profonds tels que le compartiment central ou le tractus génital se révèlent des sanctuaires de réplication virale et nécessitent pour son contrôle, une pénétration optimisée des ARV depuis la circulation générale. Nous avons d’abord évalué la pénétration de maraviroc, raltégravir et rilpivirine dans les sécrétions génitales (liquide séminal et fluide cervico-vaginal) dans le cadre de stratégies antirétrovirales conventionnelles. Nous avons montré une bonne pénétration séminale de maraviroc et raltégravir et plus faible de rilpivirine. Ensuite, nous avons évalué, d’une part, l’exposition plasmatique de darunavir/ritonavir lors de l’allègement de dose quotidienne administrée de darunavir (essai ANRS-165 DARULIGHT), puis d’autre part, la pénétration séminale de darunavir avant et après allègement. Nous avons également pu caractériser une interaction réciproque complexe d’ordre pharmacocinétique entre darunavir et ritonavir. En effet, aucune différence significative d’exposition plasmatique et séminale n’a pu être démontrée malgré la réduction de moitié de la dose de darunavir. Ces résultats mettent en avant l’absence de linéarité des expositions plasmatiques respectives de darunavir et ritonavir dans l’explication de l’interaction. Enfin, nous avons évalué la pénétration séminale d’étravirine, raltégravir et son métabolite inactif glucuroconjugué, à partir d’une stratégie de maintenance en terme d’allègement du nombre d’ARV (essai ANRS-163 ETRAL). Si aucune interaction médicamenteuse métabolique n’était à redouter entre étravirine et raltégravir, nous avons montré qu’une interaction via les transporteurs d’efflux pouvait modifier la pénétration séminale de raltégravir et de son métabolite glucuroconjugué. Au final, les résultats de l’ensemble de ces travaux ont permis de préciser l’influence de la liaison aux protéines plasmatiques et aux protéines séminales (moindre) dans la pénétration et l’accumulation des ARV dans le tractus génital mâle et l’implication potentielle des transporteurs d’efflux.

Despite the recent advances in HIV therapy, antiretroviral (ARV) treatment remains for life in order to control the HIV infection. Thus, maintenance strategies, developed to decrease the chemical burden of ARV, are evaluated to enhance the long-term tolerance with a similar efficacy to standard triple therapy. Anatomical sanctuaries such as central nervous system or genital compartment are sites of HIV replication. The penetration of ARV, from the systemic compartment to the deep compartments, is essential to control the HIV infection in these sanctuaries. First, we assessed the penetration of maraviroc, raltegravir and rilpivirine in genital fluids (seminal and…

Advisors/Committee Members: Duval, Xavier (thesis director), Peytavin, Gilles (thesis director).

Subjects/Keywords: Compartiment profond; Pénétration séminale; Transporteurs d'efflux; HIV infection; Antiretroviral; Pharmacokinetic; Deep compartment; Seminal penetration; Drug-drug interaction; Efflux transporters

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

APA (6^th Edition):

Lê, M. (2019). L'apport de l'évaluation pharmacocinétique dans le choix des antirétroviraux (nature et dose) chez la personne vivant avec le VIH : Contribution of pharmacokinetic assessment in the selection of antiretroviral therapy (type and dose) in HIV-infected patients. (Doctoral Dissertation). Sorbonne Paris Cité. Retrieved from http://www.theses.fr/2019USPCC020

Chicago Manual of Style (16^th Edition):

Lê, Minh. “L'apport de l'évaluation pharmacocinétique dans le choix des antirétroviraux (nature et dose) chez la personne vivant avec le VIH : Contribution of pharmacokinetic assessment in the selection of antiretroviral therapy (type and dose) in HIV-infected patients.” 2019. Doctoral Dissertation, Sorbonne Paris Cité. Accessed March 07, 2021. http://www.theses.fr/2019USPCC020.

MLA Handbook (7^th Edition):

Lê, Minh. “L'apport de l'évaluation pharmacocinétique dans le choix des antirétroviraux (nature et dose) chez la personne vivant avec le VIH : Contribution of pharmacokinetic assessment in the selection of antiretroviral therapy (type and dose) in HIV-infected patients.” 2019. Web. 07 Mar 2021.

Vancouver:

Lê M. L'apport de l'évaluation pharmacocinétique dans le choix des antirétroviraux (nature et dose) chez la personne vivant avec le VIH : Contribution of pharmacokinetic assessment in the selection of antiretroviral therapy (type and dose) in HIV-infected patients. [Internet] [Doctoral dissertation]. Sorbonne Paris Cité; 2019. [cited 2021 Mar 07]. Available from: http://www.theses.fr/2019USPCC020.

Council of Science Editors:

Lê M. L'apport de l'évaluation pharmacocinétique dans le choix des antirétroviraux (nature et dose) chez la personne vivant avec le VIH : Contribution of pharmacokinetic assessment in the selection of antiretroviral therapy (type and dose) in HIV-infected patients. [Doctoral Dissertation]. Sorbonne Paris Cité; 2019. Available from: http://www.theses.fr/2019USPCC020

University of Minnesota

8. Vaidhyanathan, Shruthi. Improving the Delivery of Molecularly-Targeted Agents to Effectively Treat Melanoma Brain Metastases.

Degree: PhD, Pharmaceutics, 2015, University of Minnesota

URL: http://hdl.handle.net/11299/191424

► The FDA approval of molecularly-targeted drugs that specifically targeted aberrant signaling proteins has brought about new hope for the treatment of advanced melanoma. Historically, metastatic… (more)

▼ The FDA approval of molecularly-targeted drugs that specifically targeted aberrant signaling proteins has brought about new hope for the treatment of advanced melanoma. Historically, metastatic melanoma has been an untreatable devastating disease. Two BRAF inhibitors (vemurafenib and dabrafenib), a MEK inhibitor (trametinib), and a combination of dabrafenib and trametinib are currently in use and several other drugs are in clinical development. Melanoma is known to metastasize to distant organs such as the lung, liver and brain. A critical challenge in the successful treatment of metastatic melanoma is the effective treatment of brain metastases. A significant proportion of melanoma patients have brain metastases at autopsy. It is also known that once patients develop clinical signs of CNS disease, they have an abysmally poor survival (less than 6 months). This brings about an important question about the efficacy of current drugs in treating brain metastases. The blood-brain barrier is comprised of a tight network of endothelial cells that are sealed together by tight-junction (TJ) protein complexes. The BBB also expresses several efflux transport proteins that utilize ATP to pump drug molecules against a concentration gradient. Together, the TJ proteins and ATP-dependent efflux transport proteins are known to effectively limit the permeability of several chemotherapeutics across the blood-brain barrier. Of particular interest are two efflux transporters, P-glycoprotein (P-gp) and breast-cancer resistance protein (BCRP) that are known to be highly expressed at the BBB. One of the aims of this thesis project was to understand the factors that potentially limit the efficacy of molecularly-targeted drugs in treating deadly melanoma brain metastases. Through this work, we have shown that several molecularly-targeted agents are substrates for active efflux by P-gp and BCRP. Through a series of carefully planned in vitro experiments and elegant pharmacokinetic studies in mice we conclude that the limited brain distribution of vemurafenib, dabrafenib, trametinib, and GSK2126458 (a Pi3K/mTOR inhibitor) is due to their interaction with P-gp and BCRP. We also investigated potential differences in pharmacokinetics and pharmacodynamics of vemurafenib when administered as pharmacy grade Zelboraf; versus non-pharmacy grade vemurafenib. We observed that formulation differences that affect the solubility of a drug are extremely critical to designing and interpreting meaningful pre-clinical studies. Currently, we are conducting studies in a novel melanoma mouse model in order to understand the efficacy of molecularly- targeted drugs in treating brain metastases (single agent or in-combination). The findings of this thesis provide significant insight into the selection of rational drug combinations and are highly relevant to improving the treatment of melanoma brain metastases

Subjects/Keywords: Breast cancer resistance protein; P-glycoprotein; Efflux transporters; brain distribution; Melanoma Brain Metastases; molecularly-targeted drugs; skin cancer; vemurafenib

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

APA (6^th Edition):

Vaidhyanathan, S. (2015). Improving the Delivery of Molecularly-Targeted Agents to Effectively Treat Melanoma Brain Metastases. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/191424

Chicago Manual of Style (16^th Edition):

Vaidhyanathan, Shruthi. “Improving the Delivery of Molecularly-Targeted Agents to Effectively Treat Melanoma Brain Metastases.” 2015. Doctoral Dissertation, University of Minnesota. Accessed March 07, 2021. http://hdl.handle.net/11299/191424.

MLA Handbook (7^th Edition):

Vaidhyanathan, Shruthi. “Improving the Delivery of Molecularly-Targeted Agents to Effectively Treat Melanoma Brain Metastases.” 2015. Web. 07 Mar 2021.

Vancouver:

Vaidhyanathan S. Improving the Delivery of Molecularly-Targeted Agents to Effectively Treat Melanoma Brain Metastases. [Internet] [Doctoral dissertation]. University of Minnesota; 2015. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/11299/191424.

Council of Science Editors:

Vaidhyanathan S. Improving the Delivery of Molecularly-Targeted Agents to Effectively Treat Melanoma Brain Metastases. [Doctoral Dissertation]. University of Minnesota; 2015. Available from: http://hdl.handle.net/11299/191424

9. Carrez, Romain. Implication in vivo des transporteurs pulmonaires sur la pharmacocinétique des anti-infectueux : In vivo involvement of pulmonary efflux transporters in the pharmacokinetics of anti-infectives agents.

Degree: Docteur es, Pharmacologie et sciences du médicament, 2019, Poitiers

URL: http://www.theses.fr/2019POIT1803

► Face à la pénurie de nouveaux anti-infectieux et à l’émergence toujours plus importante d’agents infectieux multi-résistants, il est primordial de mieux utiliser l’arsenal thérapeutique à… (more)

▼ Face à la pénurie de nouveaux anti-infectieux et à l’émergence toujours plus importante d’agents infectieux multi-résistants, il est primordial de mieux utiliser l’arsenal thérapeutique à notre disposition. Cela peut passer par l’utilisation de nouvelles voies d’administration afin d’agir plus efficacement localement. Pour traiter des infections pulmonaires, l’inhalation ou la nébulisation apparaissent comme des voies logiquement intéressantes. Il a été montré précédemment que les molécules plutôt hydrophiles étaient des bonnes candidates à cette voie d’administration car l’épithélium pulmonaire leur était peu perméable et que le principe actif était séquestré au niveau du poumon. A l’inverse, pour les composés lipophiles qui diffusent rapidement à travers l’épithélium, l’administration pulmonaire ne présente que peu d’intérêt thérapeutique. La situation se complexifie dans le cas de la nébulisation de promédicaments et/ou lorsque des pompes d’efflux interviennent dans la distribution pulmonaire des anti-infectieux. Afin de mieux caractériser le rôle des pompes d’efflux dans la distribution pulmonaire des anti-infectieux in vitro et leur impact in vivo, la distribution pulmonaire de plusieurs anti-infectieux a été évaluée selon un protocole standardisé chez le rat, permettant de mesurer et donc de comparer les concentrations libres plasmatiques et dans le liquide épithélial pulmonaire (ELF) après administrations systémique et intratrachéale. Le premier travail porte sur la distribution pulmonaire de l’oseltamivir, un anti-viral actif contre la grippe, qui est administré sous forme de promédicament (oseltamivir phosphate (OP)). Il a été montré in vitro que l’OP (non actif) est substrat de pompes d’efflux et que ce transport actif se caractérise in vivo par des concentrations locales plus élevées d’OP dans l’ELF que dans le plasma quelle que soit la voie d’administration (intraveineuse ou nébulisation). Cependant, ces fortes concentrations pulmonaires en promédicament n’ont que peu d’effet sur les concentrations pulmonaires en molécule active (oseltamivir carboxylate (OC)), du fait d’une faible conversion locale en composé actif et de la perméabilité pulmonaire de l’OC. La deuxième étude présente le cas des oxazolidinones (linézolide et tédizolide) utilisées pour traiter les infections à Gram positif pour lesquels des études in vivo préalablement réalisées chez l’homme avaient montrées des concentrations locales (ELF) supérieures aux concentrations plasmatiques après administration orale. Ces données ont été retrouvées chez le rat selon notre protocole standardisé et complétées avec des données après nébulisation, suggérant un rôle majeur des transporteurs dans ladiffusion pulmonaire notamment du tedizolide. Cependant, les études de perméabilité membranaire et d’inhibition in vitro réalisées sur un modèle cellulaire (NCI-H441) n’ont pas pu mettre en évidence le rôle de ces transporteurs d’efflux sur les concentrations pulmonaires élevées. D’autres explications ont été envisagées comme la liaison à des protéines dans… Advisors/Committee Members: Marchand, Sandrine (thesis director), Brillault, Julien (thesis director).

Subjects/Keywords: Modélisation pharmacocinétique; Poumon; Transporteur d'efflux; Nébulisation oseltamivir; Oxazolidinones; Pharmacokinetics modeling; Lung; Efflux transporters; Nebulisation; Oseltamivir; Oxazolidinones; 615.792; 571.64; 573.25

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

APA (6^th Edition):

Carrez, R. (2019). Implication in vivo des transporteurs pulmonaires sur la pharmacocinétique des anti-infectueux : In vivo involvement of pulmonary efflux transporters in the pharmacokinetics of anti-infectives agents. (Doctoral Dissertation). Poitiers. Retrieved from http://www.theses.fr/2019POIT1803

Chicago Manual of Style (16^th Edition):

Carrez, Romain. “Implication in vivo des transporteurs pulmonaires sur la pharmacocinétique des anti-infectueux : In vivo involvement of pulmonary efflux transporters in the pharmacokinetics of anti-infectives agents.” 2019. Doctoral Dissertation, Poitiers. Accessed March 07, 2021. http://www.theses.fr/2019POIT1803.

MLA Handbook (7^th Edition):

Carrez, Romain. “Implication in vivo des transporteurs pulmonaires sur la pharmacocinétique des anti-infectueux : In vivo involvement of pulmonary efflux transporters in the pharmacokinetics of anti-infectives agents.” 2019. Web. 07 Mar 2021.

Vancouver:

Carrez R. Implication in vivo des transporteurs pulmonaires sur la pharmacocinétique des anti-infectueux : In vivo involvement of pulmonary efflux transporters in the pharmacokinetics of anti-infectives agents. [Internet] [Doctoral dissertation]. Poitiers; 2019. [cited 2021 Mar 07]. Available from: http://www.theses.fr/2019POIT1803.

Council of Science Editors:

Carrez R. Implication in vivo des transporteurs pulmonaires sur la pharmacocinétique des anti-infectueux : In vivo involvement of pulmonary efflux transporters in the pharmacokinetics of anti-infectives agents. [Doctoral Dissertation]. Poitiers; 2019. Available from: http://www.theses.fr/2019POIT1803

University of Manchester

10. Djoukhadar, Ibrahim Khalil. Measuring and Modifying Temozolomide Delivery in Brain Tumours.

Degree: 2017, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309634

►

Glioblastoma (GBM) is the most common aggressive primary brain tumour in adults. Despite various recent treatment advances, prognosis and survival rates remain dismal. A potential… (more)

▼

Glioblastoma (GBM) is the most common aggressive primary brain tumour in adults. Despite various recent treatment advances, prognosis and survival rates remain dismal. A potential explanation for such poor outcomes is the high invasive nature of glioma cells, which enable them to invade areas of the brain where the blood-brain barrier may still be intact. This could explain the frequently encountered tumour recurrences that occur at the edges of the original tumour or at the surgical resection margins. Another potential explanation for such poor outcomes is the blood-brain barrier (BBB), which prevents delivery of effective chemotherapy into the brain. Furthermore, efflux transporters at the BBB can also restrict drug delivery. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two efflux transporters that work closely together as efflux pumps for a variety of anticancer drugs. Temozolomide (TMZ) is the central chemotherapy agent used in the treatment of malignant brain tumours but interestingly, its relationship with P-gp and BCRP remains poorly understood. The ultimate aim of this thesis is to develop an imaging method for measuring the effects of strategies modifying Temozolomide (TMZ) delivery into the brain and brain tumours. An in-vitro BBB model was developed and validated. This was then used to conduct TMZ transport studies, which showed a trend for TMZ to be transported by P-gp and BCRP at clinically relevant concentrations. In order to confirm these results, dynamic small animal positron emission tomography (PET) with [11C]TMZ was also performed in wild-type and in mice lacking P-gp, BCRP or both transporters as well as in wild-type mice treated with the efflux transporter inhibitor Tariquidar (TQD). Scans confirmed higher delivery of [11C]TMZ in mice lacking P-gp, BCRP and both transporters. Similar results were noted in wild type mice following the pharmacological inhibition of P-gp and BCRP. A human glioma model in mice was derived by intracranial injection of human U87 glioma cells in thirty-five athymic female mice. Animals were treated with TMZ alone, TQD alone or combination therapy (TMZ and TQD). Response to treatment was evaluated by performing volumetric tumour measurement using MRI. Combination therapy was shown to be superior achieving significant early and sustained response in tumours when compared with TMZ alone treatment. Finally, PET imaging was used with the known P-gp substrate (R)-[11C]verapamil to demonstrate the functional activity of P-gp in five high-grade glioma patients. This approach was shown to be a suitable non-invasive imaging method for visualising P-gp function in patients with brain tumours and highlighted the heterogeneity of the functional activity of P-gp in these patients.

N/A

Advisors/Committee Members: WILLIAMS, KAYE KJ, PENNY, JEFFREY JI, ASSELIN, MARIE-CLAUDE M, Jackson, Alan, Williams, Kaye, Penny, Jeffrey, Asselin, Marie-Claude.

Subjects/Keywords: Brain Tumours; Neuro-oncology; Imaging; blood brain barrier; Temozolomide; efflux transporters; P-glycoprotein; Breast Cancer Resistance protein

Record Details Similar Records Cite « Share

❌

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

APA (6^th Edition):

Djoukhadar, I. K. (2017). Measuring and Modifying Temozolomide Delivery in Brain Tumours. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309634

Chicago Manual of Style (16^th Edition):

Djoukhadar, Ibrahim Khalil. “Measuring and Modifying Temozolomide Delivery in Brain Tumours.” 2017. Doctoral Dissertation, University of Manchester. Accessed March 07, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309634.

MLA Handbook (7^th Edition):

Djoukhadar, Ibrahim Khalil. “Measuring and Modifying Temozolomide Delivery in Brain Tumours.” 2017. Web. 07 Mar 2021.

Vancouver:

Djoukhadar IK. Measuring and Modifying Temozolomide Delivery in Brain Tumours. [Internet] [Doctoral dissertation]. University of Manchester; 2017. [cited 2021 Mar 07]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309634.

Council of Science Editors:

Djoukhadar IK. Measuring and Modifying Temozolomide Delivery in Brain Tumours. [Doctoral Dissertation]. University of Manchester; 2017. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309634

University of Manchester

11. Djoukhadar, Ibrahim. Measuring and modifying Temozolomide delivery in brain tumours.

Degree: PhD, 2017, University of Manchester

URL: https://www.research.manchester.ac.uk/portal/en/theses/measuring-and-modifying-temozolomide-delivery-in-brain-tumours(5ffb33be-c2e9-4c2b-bd40-b3e439b2d8f8).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.822947

► Glioblastoma (GBM) is the most common aggressive primary brain tumour in adults. Despite various recent treatment advances, prognosis and survival rates remain dismal. A potential… (more)

▼ Glioblastoma (GBM) is the most common aggressive primary brain tumour in adults. Despite various recent treatment advances, prognosis and survival rates remain dismal. A potential explanation for such poor outcomes is the high invasive nature of glioma cells, which enable them to invade areas of the brain where the blood-brain barrier may still be intact. This could explain the frequently encountered tumour recurrences that occur at the edges of the original tumour or at the surgical resection margins. Another potential explanation for such poor outcomes is the blood-brain barrier (BBB), which prevents delivery of effective chemotherapy into the brain. Furthermore, efflux transporters at the BBB can also restrict drug delivery. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two efflux transporters that work closely together as efflux pumps for a variety of anticancer drugs. Temozolomide (TMZ) is the central chemotherapy agent used in the treatment of malignant brain tumours but interestingly, its relationship with P-gp and BCRP remains poorly understood. The ultimate aim of this thesis is to develop an imaging method for measuring the effects of strategies modifying Temozolomide (TMZ) delivery into the brain and brain tumours. An in-vitro BBB model was developed and validated. This was then used to conduct TMZ transport studies, which showed a trend for TMZ to be transported by P-gp and BCRP at clinically relevant concentrations. In order to confirm these results, dynamic small animal positron emission tomography (PET) with [11C]TMZ was also performed in wild-type and in mice lacking P-gp, BCRP or both transporters as well as in wild-type mice treated with the efflux transporter inhibitor Tariquidar (TQD). Scans confirmed higher delivery of [11C]TMZ in mice lacking P-gp, BCRP and both transporters. Similar results were noted in wild type mice following the pharmacological inhibition of P-gp and BCRP. A human glioma model in mice was derived by intracranial injection of human U87 glioma cells in thirty-five athymic female mice. Animals were treated with TMZ alone, TQD alone or combination therapy (TMZ and TQD). Response to treatment was evaluated by performing volumetric tumour measurement using MRI. Combination therapy was shown to be superior achieving significant early and sustained response in tumours when compared with TMZ alone treatment. Finally, PET imaging was used with the known P-gp substrate (R)-[11C]verapamil to demonstrate the functional activity of P-gp in five high-grade glioma patients. This approach was shown to be a suitable non-invasive imaging method for visualising P-gp function in patients with brain tumours and highlighted the heterogeneity of the functional activity of P-gp in these patients.

Subjects/Keywords: Breast Cancer Resistance protein; P-glycoprotein; efflux transporters; Temozolomide; Imaging; Neuro-oncology; Brain Tumours; blood brain barrier

Record Details Similar Records Cite « Share

❌

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

APA (6^th Edition):

Djoukhadar, I. (2017). Measuring and modifying Temozolomide delivery in brain tumours. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/measuring-and-modifying-temozolomide-delivery-in-brain-tumours(5ffb33be-c2e9-4c2b-bd40-b3e439b2d8f8).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.822947

Chicago Manual of Style (16^th Edition):

Djoukhadar, Ibrahim. “Measuring and modifying Temozolomide delivery in brain tumours.” 2017. Doctoral Dissertation, University of Manchester. Accessed March 07, 2021. https://www.research.manchester.ac.uk/portal/en/theses/measuring-and-modifying-temozolomide-delivery-in-brain-tumours(5ffb33be-c2e9-4c2b-bd40-b3e439b2d8f8).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.822947.

MLA Handbook (7^th Edition):

Djoukhadar, Ibrahim. “Measuring and modifying Temozolomide delivery in brain tumours.” 2017. Web. 07 Mar 2021.

Vancouver:

Djoukhadar I. Measuring and modifying Temozolomide delivery in brain tumours. [Internet] [Doctoral dissertation]. University of Manchester; 2017. [cited 2021 Mar 07]. Available from: https://www.research.manchester.ac.uk/portal/en/theses/measuring-and-modifying-temozolomide-delivery-in-brain-tumours(5ffb33be-c2e9-4c2b-bd40-b3e439b2d8f8).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.822947.

Council of Science Editors:

Djoukhadar I. Measuring and modifying Temozolomide delivery in brain tumours. [Doctoral Dissertation]. University of Manchester; 2017. Available from: https://www.research.manchester.ac.uk/portal/en/theses/measuring-and-modifying-temozolomide-delivery-in-brain-tumours(5ffb33be-c2e9-4c2b-bd40-b3e439b2d8f8).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.822947

12. Viana Soares, Ricardo. Study of the antiepileptic drugs transport through the immature blood-brain barrier : Etude du passage des médicaments antiépileptiques à travers la barrière hémato-encéphalique.

Degree: Docteur es, Pharmacologie, 2015, Sorbonne Paris Cité

URL: http://www.theses.fr/2015USPCB087

►

La résistance aux médicaments antiépileptiques (MAEs) est un des problèmes majeurs des épilepsies infantiles, comme par exemple le syndrome de Dravet. La pharmacoresistance de l’épilepsie… (more)

▼

La résistance aux médicaments antiépileptiques (MAEs) est un des problèmes majeurs des épilepsies infantiles, comme par exemple le syndrome de Dravet. La pharmacoresistance de l’épilepsie pourrait s’expliquer par une diminution du passage des MAEs dans le cerveau, à travers la Barrière Hémato-Encéphalique (BHE). La BHE comporte des transporteurs des familles « ATP-binding cassette » (ABC) et « SoLute Carrier » (SLC) localisés au niveau de la membrane des cellules endothéliales qui contrôlent leur passage entre le sang et le cerveau. La pharmacoresistance des épilepsies a été associée à ces transporteurs car des MAEs ont été identifiés comme substrats de transporteurs comme la glycoprotéine-P (P-gP) et la « Breast Cancer Resistance Protein » (BCRP). L’hypothèse de cette relation est confortée par l’observation de l’augmentation de l’expression de ces transporteurs d’efflux dans le foyer épileptogène et par l’identification des polymorphismes dans les gènes des transporteurs chez des patients pharmacorésistants. L’interaction au cours du développement cérébral entre les cellules endothéliales et les neurones et astrocytes pourrait modifier le profil des transporteurs de la BHE. Les MAEs sont aussi connus pour être soit des inducteurs, soit des inhibiteurs des enzymes du métabolisme des médicaments et des transporteurs membranaires. Ces données nous permettent de faire les hypothèses suivantes: 1) La BHE en développement présente un profil de transporteurs différent de la BHE mature qui pourrait modifier le passage des MAEs vers le cerveau ; et 2) le traitement chronique administré au cours du syndrome de Dravet pourrait changer le phénotype des transporteurs de la BHE en développement. Nous résultats ont montré que la P-gP et la BCRP augment leur expression au cours du développement. La maturation de la BHE a aussi un impact sur le passage des MAEs étudiés. Nous avons constaté une augmentation de l’expression des différents transporteurs ABC et SLC étudiés pendant le développement de la BHE, suite au traitement chronique avec la thérapie du Syndrome de Dravet. L’acide valproïque, un des MAEs utilisé dans ce traitement, diminue l’activité d’efflux de la P-gP chez les rats en développement et adultes, ce qui a été confirmé dans un modèle in-vitro de BHE immature. Ces résultats mettent en évidence l’interaction entre la BHE en développement et le traitement chronique par les MAEs peut modifier leur distribution au niveau du cerveau et la réponse aux MAEs.

Resistance to Antiepileptic Drugs (AEDs) has been a major concern in infantile epilepsies such as for example the Dravet Syndrome. One hypothesis concerning the pharmacoresistance in epilepsy is that a decreased delivery of these drugs to the brain may occur in relation to changes in the Blood-Brain Barrier (BBB) function. BBB exhibits ATP-binding cassette (ABC) and SoLute Carrier (SLC) transporters at the surface of endothelial cells that control the blood-brain transport. Pharmacoresistance in epilepsy may be linked to changes in the functions of these transporters…

Advisors/Committee Members: Pons, Gérard (thesis director), Mabondzo, Aloïse (thesis director).

Subjects/Keywords: Pharmacorésistance; Médicaments antiépileptiques; Syndrome de Dravet; Barrière hémato-encéphalique; Transporteurs d’efflux; Pharmacoresistance; Antiepileptic drugs; Dravet syndrome; Blood-brain barrier; Efflux transporters; 615.78

Record Details Similar Records Cite « Share

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

APA (6^th Edition):

Viana Soares, R. (2015). Study of the antiepileptic drugs transport through the immature blood-brain barrier : Etude du passage des médicaments antiépileptiques à travers la barrière hémato-encéphalique. (Doctoral Dissertation). Sorbonne Paris Cité. Retrieved from http://www.theses.fr/2015USPCB087

Chicago Manual of Style (16^th Edition):

Viana Soares, Ricardo. “Study of the antiepileptic drugs transport through the immature blood-brain barrier : Etude du passage des médicaments antiépileptiques à travers la barrière hémato-encéphalique.” 2015. Doctoral Dissertation, Sorbonne Paris Cité. Accessed March 07, 2021. http://www.theses.fr/2015USPCB087.

MLA Handbook (7^th Edition):

Viana Soares, Ricardo. “Study of the antiepileptic drugs transport through the immature blood-brain barrier : Etude du passage des médicaments antiépileptiques à travers la barrière hémato-encéphalique.” 2015. Web. 07 Mar 2021.

Vancouver:

Viana Soares R. Study of the antiepileptic drugs transport through the immature blood-brain barrier : Etude du passage des médicaments antiépileptiques à travers la barrière hémato-encéphalique. [Internet] [Doctoral dissertation]. Sorbonne Paris Cité; 2015. [cited 2021 Mar 07]. Available from: http://www.theses.fr/2015USPCB087.

Council of Science Editors:

Viana Soares R. Study of the antiepileptic drugs transport through the immature blood-brain barrier : Etude du passage des médicaments antiépileptiques à travers la barrière hémato-encéphalique. [Doctoral Dissertation]. Sorbonne Paris Cité; 2015. Available from: http://www.theses.fr/2015USPCB087

13. Wang, Jie. Fibroblast growth factor-2 protects neonatal rat cardiac myocytes from doxorubicin-induced damage via protein kinase C- dependent effects on efflux drug transporters.

Degree: Physiology, 2013, University of Manitoba

URL: http://hdl.handle.net/1993/18318

► Introduction: Therapeutic agents like doxorubicin, an anthracycline antibiotic drug, are widely used in cancer chemotherapy. The use of doxorubicin is limited however by an increased… (more)

▼ Introduction: Therapeutic agents like doxorubicin, an anthracycline antibiotic drug, are widely used in cancer chemotherapy. The use of doxorubicin is limited however by an increased risk of cardiac damage as a side effect, and an increased cancer cell drug resistance mediated by efflux drug transporters. Strategies are needed to protect the heart and still allow the benefits of drug treatment. “Basic” fibroblast growth factor-2 (FGF-2) is a multi-functional protein. It is angiogenic and cardioprotective against ischemia-reperfusion injury. FGF-2 can also regulate cancer cell drug resistance or sensitivity, however, so far, there is no evidence that FGF-2 protects against doxorubicin-induced cardiac damage through effects on efflux drug transporter levels or function. Aims: To investigate whether: (1) FGF-2 can increase resistance to doxorubicin-induced neonatal rat cardiac myocyte damage; and if so whether (2) an effect on efflux drug transporters might contribute to this cardioprotection by FGF-2. Methods: Neonatal rat cardiac myocyte cultures were treated with doxorubicin in the absence or presence of pre-treatment with FGF-2. To assess cell damage: (i) culture medium was tested for lactate dehydrogenase (LDH) activity as an indication of plasma membrane disruption; (ii) cells were stained with fluorescent apoptosis and necrosis biomarkers as well as (iii) terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and acridine orange to assess DNA fragmentation or compaction. The role of FGF receptor (FGFR) or protein kinase C (PKC) was addressed through use of inhibitors including SU5402, or chelerythrine as well as bisindomaleimide. Multidrug resistance gene 1a and 1b (MDR1a, 1b), multidrug resistance gene 2 (MDR2) and multidrug resistance-related protein 1 (MRP1) gene expression, as well as the function of MDRs and MRPs protein products were assessed by real-time reverse transcriptase-polymerase chain reaction (qPCR), as well as retention/extrusion of (fluorescent) doxorubicin/calcein in cardiac myocytes, respectively. Efflux drug transporter inhibitors, including 20 µM cyclosporine A (CsA), 2 µM verapamil and 1 µM Tariquidar (XR9576) were used to asssess for a direct effect of FGF-2 on transporter function. Fluorescence-activated cell sorting (FACS) was used to measure fluorescent doxorubicin/calcein levels inside treated cardiac myocytes. Results: Doxorubicin increased the incidence of programmed cell death, DNA damage, and lysosome and LDH activity, while decreasing cell number at 24 hours. FGF-2 prevented the detrimental effects of doxorubicin. In turn, the protective effects of FGF-2 were blocked in the presence of FGFR or PKC inhibitors. FGF-2 treatment significantly increased MDR1a, MDR1b, MDR2, MRP1 RNA levels by qPCR, and protein levels as assessed by function, and specifically extrusion of doxorubicin/calcein, in the presence of doxorubicin when compared to doxorubicin treatment alone. Furthermore, inhibition of efflux drug transporters with CsA and Tariquidar (XR9576) significantly… Advisors/Committee Members: Cattini, Peter A. (Physiology) (supervisor), Kardami, Elissavet (Physiology) Czubryt, Michael (Physiology) Nachtigal, Mark (Biochemistry and Medical Genetics) (examiningcommittee).

Subjects/Keywords: FGF-2; Doxorubicin; efflux drug transporters; PKC; neonatal rat cardiomyocytes

…resistance mediated by efflux drug transporters. Strategies are needed to protect the heart and… …damage; and if so whether (2) an effect on efflux drug transporters might contribute… …Furthermore, inhibition of efflux drug transporters with CsA and Tariquidar (XR9576)… …7 Figure 1. 3 - ATP-binding cassette (ABC) efflux transporters… …multidrug resistance due to an increase in efflux drug transporters such as multidrug resistance…

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APA (6^th Edition):

Wang, J. (2013). Fibroblast growth factor-2 protects neonatal rat cardiac myocytes from doxorubicin-induced damage via protein kinase C- dependent effects on efflux drug transporters. (Masters Thesis). University of Manitoba. Retrieved from http://hdl.handle.net/1993/18318

Chicago Manual of Style (16^th Edition):

Wang, Jie. “Fibroblast growth factor-2 protects neonatal rat cardiac myocytes from doxorubicin-induced damage via protein kinase C- dependent effects on efflux drug transporters.” 2013. Masters Thesis, University of Manitoba. Accessed March 07, 2021. http://hdl.handle.net/1993/18318.

MLA Handbook (7^th Edition):

Wang, Jie. “Fibroblast growth factor-2 protects neonatal rat cardiac myocytes from doxorubicin-induced damage via protein kinase C- dependent effects on efflux drug transporters.” 2013. Web. 07 Mar 2021.

Vancouver:

Wang J. Fibroblast growth factor-2 protects neonatal rat cardiac myocytes from doxorubicin-induced damage via protein kinase C- dependent effects on efflux drug transporters. [Internet] [Masters thesis]. University of Manitoba; 2013. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/1993/18318.

Council of Science Editors:

Wang J. Fibroblast growth factor-2 protects neonatal rat cardiac myocytes from doxorubicin-induced damage via protein kinase C- dependent effects on efflux drug transporters. [Masters Thesis]. University of Manitoba; 2013. Available from: http://hdl.handle.net/1993/18318

University of Minnesota

14. Li, Li. Active efflux transport and CNS distribution of the novel antifolate pemetrexed.

Degree: PhD, Pharmaceutics, 2010, University of Minnesota

URL: http://purl.umn.edu/61952

► Pemetrexed (PMX, Alimta®) is a novel multi-targeted antifolate approved for the treatment of malignant pleural mesothelioma and non-small cell lung cancer (NSCLC). Given the high… (more)

▼ Pemetrexed (PMX, Alimta®) is a novel multi-targeted antifolate approved for the treatment of malignant pleural mesothelioma and non-small cell lung cancer (NSCLC). Given the high incidence of brain metastasis in NSCLC patients and wide use of the classic antifolate, methotrexate (MTX), in primary CNS lymphoma, the clinical use of PMX may eventually include the treatment of CNS tumors. However, previous studies in our laboratory indicated that, like MTX, PMX has difficulty in penetrating across the blood-brain barrier (BBB). Factors limiting the CNS distribution of PMX remain unidentified. One important determinant of CNS distribution is efflux transport by BBB transporters. The overall objective of this study was to characterize the brain-to-blood efflux transport of PMX and to examine role of BBB efflux transporters such as BCRP, MRP2 and other organic anion transporters in brain distribution of PMX. The interaction of PMX with BCRP was examined in vitro and in vivo. In vitro results revealed that PMX is a substrate for BCRP-mediated transport. In vivo examination indicated that deletion of Bcrpl has little influence on brain penetration of PMX. Using the brain efflux index method, the mechanism responsible for the brain efflux of PMX and MTX was investigated. The results revealed that brain elimination half-life of PMX and MTX were 48 and 32 minutes, respectively and both PMX and MTX undergo saturable efflux transport across the BBB. MRP2 does not play a role in the brain distribution of either antifolate. However, BCRP makes a significant contribution to brain elimination of MTX, but not PMX. In addition, it was observed that brain-to-blood transport of PMX and MTX was markedly inhibited by probenecid and benzylpenicillin, suggesting the involvement of organic anion transporters, possibly OAT3. Given the knowledge that solid tumors and some physiological barriers have an acidic extracellular environment, the effect of pH on transport activity of BCRP for PMX was examined. In addition, the molecular basis of the observed pH-dependency in BCRP transport activity was explored based on the recent homology model of BCRP. This study has important implications in the handling of PMX and other chemotherapy drug molecules in the acidic environment of tumors and in the distribution and elimination of the drug molecules. Studies presented in this dissertation provide useful information about the specific mechanisms involved in limiting the brain penetration of PMX and MTX. This new knowledge will help in formulating strategies to improve CNS delivery of these antifolates and maylead to more successful treatment of primary and secondary CNS tumors.

Subjects/Keywords: Antifolate; Blood-Brain Barrier; Breast Cancer Resistance Protein; Efflux transporters; Pemetrexed; Pharmacokinetics; Pharmaceutics.

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

APA (6^th Edition):

Li, L. (2010). Active efflux transport and CNS distribution of the novel antifolate pemetrexed. (Doctoral Dissertation). University of Minnesota. Retrieved from http://purl.umn.edu/61952

Chicago Manual of Style (16^th Edition):

Li, Li. “Active efflux transport and CNS distribution of the novel antifolate pemetrexed.” 2010. Doctoral Dissertation, University of Minnesota. Accessed March 07, 2021. http://purl.umn.edu/61952.

MLA Handbook (7^th Edition):

Li, Li. “Active efflux transport and CNS distribution of the novel antifolate pemetrexed.” 2010. Web. 07 Mar 2021.

Vancouver:

Li L. Active efflux transport and CNS distribution of the novel antifolate pemetrexed. [Internet] [Doctoral dissertation]. University of Minnesota; 2010. [cited 2021 Mar 07]. Available from: http://purl.umn.edu/61952.

Council of Science Editors:

Li L. Active efflux transport and CNS distribution of the novel antifolate pemetrexed. [Doctoral Dissertation]. University of Minnesota; 2010. Available from: http://purl.umn.edu/61952

INP Toulouse

15. Albérich, Mélanie. Impact de l'ivermectine sur les systèmes de détoxification des xénobiotiques : régulations chez l'hôte et chez le nématode : Impact of ivermectin on xenobiotic detoxification systems : regulations in host and nematode.

Degree: Docteur es, Pathologie, Toxicologie, Génétique et Nutrition, 2014, INP Toulouse

URL: http://www.theses.fr/2014INPT0102

►

Les infections par les nématodes gastro-intestinaux entrainent des baisses en productions animales et des pertes économiques majeures pour les éleveurs. Les lactones macrocycliques (LMs) sont… (more)

▼

Les infections par les nématodes gastro-intestinaux entrainent des baisses en productions animales et des pertes économiques majeures pour les éleveurs. Les lactones macrocycliques (LMs) sont parmi les antiparasitaires les plus utilisés dans la lutte contre les nématodes gastro-intestinaux en médecine vétérinaire. De part une utilisation intensive, des résistances aux LMs chez les parasites gastro-intestinaux se sont développées au sein des élevages du monde entier mettant en péril l'efficacité thérapeutique de ces molécules. Par ailleurs, le développement de nouveaux antiparasitaires est limité. Ainsi, un des enjeux pour assurer le contrôle de ces parasites est de ralentir les phénomènes de résistance aux LMs afin de prolonger leur efficacité. Le succès d'une telle stratégie repose sur les connaissances précises des mécanismes impliqués dans la résistance. Parmi eux, la modulation des systèmes de détoxification est décrite lors de phénomènes de résistance aux LMs. Au cours de ces travaux, nous avons étudiés la régulation des systèmes de détoxification, en réponse à l'ivermectine chez l'hôte. Nous avons montré, en comparaison à une administration unique, qu'une administration répétée d'ivermectine par voie orale chez la souris est responsable de l'induction de l'expression de certains gènes transporteurs ABC et cytochromes impliqués dans son métabolisme. Ceci entraîne, à la fois, une diminution de la concentration de la molécule parentale et une augmentation de la teneur de son métabolite principal dans le plasma et l'intestin. Ensuite, nous avons étudié l'implication des mécanismes de régulation des systèmes de détoxification, et notamment les récepteurs nucléaires, dans la tolérance à l'ivermectine chez le nématode C.elegans. Nous avons montré que le récepteur nucléaire nhr-a est important pour la tolérance et le développement de la résistance à l'ivermectine. Enfin, nous avons étudié l'impact d'inhibiteurs des transporteurs ABC sur l'efficacité de l'ivermectine. Nous avons mis en évidence la capacité de certains flavonoïdes et de l'ivermectine aglycone à potentialiser l'efficacité de l'ivermectine chez le nématode. Une exposition d'ivermectine induit la surexpression des systèmes de détoxification chez l'hôte. Ceci pourrait être la base des mécanismes moléculaires de la résistance chez le nématode. Cibler les systèmes de détoxification ou les mécanismes de résistance, par des inhibiteurs adaptés, représente une stratégie pertinente pour potentialiser l'efficacité de l'ivermectine.

Infections with gastrointestinal nematodes (GINs) in livestock leads to major losses in production and consequently impact economically farmers. Their intensive use has led to widespread anthelmintic resistance which is nowadays the main threat on the sustainable control of GINs in livestock. The development of new anthelmintic is limited due to the cost of such process. Then, the challenge remains in optimizing the use of existing molecules. Therefore, it is urgent to limit and control MLs resistance in order to extend their efficacy…

Advisors/Committee Members: Lespine, Anne (thesis director), Ménez-Berlioz, Cécile (thesis director).

Subjects/Keywords: Lactones macrocycliques anthelminthiques; Ivermectine; Transporteurs ABC d'efflux; Cytochromes P450; Foie; Intestin; Modèles murins; Caenorhabditis elegans; Récepteurs nucléaires; Flavonoïdes; Ivermectine aglycone; Résistance; Macrocyclic lactone; Ivermectin; ABC efflux transporters; Cytochromes; Liver; Intestine; Mice; Caenorhabditis elegans; Nuclear receptors; Flavonoïds; Ivermectin aglycone; Resistance

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

APA (6^th Edition):

Albérich, M. (2014). Impact de l'ivermectine sur les systèmes de détoxification des xénobiotiques : régulations chez l'hôte et chez le nématode : Impact of ivermectin on xenobiotic detoxification systems : regulations in host and nematode. (Doctoral Dissertation). INP Toulouse. Retrieved from http://www.theses.fr/2014INPT0102

Chicago Manual of Style (16^th Edition):

Albérich, Mélanie. “Impact de l'ivermectine sur les systèmes de détoxification des xénobiotiques : régulations chez l'hôte et chez le nématode : Impact of ivermectin on xenobiotic detoxification systems : regulations in host and nematode.” 2014. Doctoral Dissertation, INP Toulouse. Accessed March 07, 2021. http://www.theses.fr/2014INPT0102.

MLA Handbook (7^th Edition):

Albérich, Mélanie. “Impact de l'ivermectine sur les systèmes de détoxification des xénobiotiques : régulations chez l'hôte et chez le nématode : Impact of ivermectin on xenobiotic detoxification systems : regulations in host and nematode.” 2014. Web. 07 Mar 2021.

Vancouver:

Albérich M. Impact de l'ivermectine sur les systèmes de détoxification des xénobiotiques : régulations chez l'hôte et chez le nématode : Impact of ivermectin on xenobiotic detoxification systems : regulations in host and nematode. [Internet] [Doctoral dissertation]. INP Toulouse; 2014. [cited 2021 Mar 07]. Available from: http://www.theses.fr/2014INPT0102.

Council of Science Editors:

Albérich M. Impact de l'ivermectine sur les systèmes de détoxification des xénobiotiques : régulations chez l'hôte et chez le nématode : Impact of ivermectin on xenobiotic detoxification systems : regulations in host and nematode. [Doctoral Dissertation]. INP Toulouse; 2014. Available from: http://www.theses.fr/2014INPT0102

University of Queensland

16. Varasteh Moradi, Shayli. Improving the bioavailability and stability of luteinizing hormone-releasing hormone (LHRH) analogues.

Degree: School of Chemistry and Molecular Biosciences, 2015, University of Queensland

URL: http://espace.library.uq.edu.au/view/UQ:370230

Subjects/Keywords: LHRH; Glycosylation; Peptide; Oral delivery; Prostate cancer; Glucose transporters; Efflux pump systems; Bioavailability; LH and FSH release; 0304 Medicinal and Biomolecular Chemistry; 1115 Pharmacology and Pharmaceutical Sciences

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

APA (6^th Edition):

Varasteh Moradi, S. (2015). Improving the bioavailability and stability of luteinizing hormone-releasing hormone (LHRH) analogues. (Thesis). University of Queensland. Retrieved from http://espace.library.uq.edu.au/view/UQ:370230

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):

Varasteh Moradi, Shayli. “Improving the bioavailability and stability of luteinizing hormone-releasing hormone (LHRH) analogues.” 2015. Thesis, University of Queensland. Accessed March 07, 2021. http://espace.library.uq.edu.au/view/UQ:370230.

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

MLA Handbook (7^th Edition):

Varasteh Moradi, Shayli. “Improving the bioavailability and stability of luteinizing hormone-releasing hormone (LHRH) analogues.” 2015. Web. 07 Mar 2021.

Vancouver:

Varasteh Moradi S. Improving the bioavailability and stability of luteinizing hormone-releasing hormone (LHRH) analogues. [Internet] [Thesis]. University of Queensland; 2015. [cited 2021 Mar 07]. Available from: http://espace.library.uq.edu.au/view/UQ:370230.

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

Council of Science Editors:

Varasteh Moradi S. Improving the bioavailability and stability of luteinizing hormone-releasing hormone (LHRH) analogues. [Thesis]. University of Queensland; 2015. Available from: http://espace.library.uq.edu.au/view/UQ:370230

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

University of Southern California

17. 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 March 07, 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. 07 Mar 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 Mar 07]. 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

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