subject:(Drug Induction)

University of British Columbia

1. Gontovnick, Larry Stuart. Nuclear localization and induction of rat hepatic drug metabolizing enzymes.

Degree: PhD, Pharmaceutical Sciences, 1981, University of British Columbia

► The nucleus may be the critical site for the activation of chemical carcinogens, and subsequently the initiation of neoplasia. However, isolated nuclei may be contaminated… (more)

▼ The nucleus may be the critical site for the activation of chemical carcinogens, and subsequently the initiation of neoplasia. However, isolated nuclei may be contaminated with endoplasmic reticulum, the major site of the drug metabolizing enzymes. One of the objectives of the present study was to determine whether the enzymes in isolated rat hepatic nuclei were of nuclear origin and, if so, to compare these enzymes with those in the microsomal fraction. The selective manipulation of nuclear enzymes would be a useful tool in determining their role in cellular toxicity. Recentrifugation experiments, with aryl hydrocarbon hydroxylase (AHH) activity as a marker, showed that isolated nuclei were not contaminated with endoplasmic reticulum in the form of microsomes formed upon homogenization. However, small "tags" of endoplasmic reticulum, continuous with the nuclear membrane, and indiscernable in electron micrographs, could remain following centrifugation and account for all of the measurable enzyme activity in the isolated nuclei. It was reasoned that if endoplasmic reticulum accounted for all of the activity, then the ratio of nuclear to microsomal activity for all enzymes determined should be the same. The ratios of epoxide hydrolase and AHH were found to differ in the two fractions. The simplest interpretation of these data was that drug metabolizing enzymes existed in the nuclei. However, the distribution of drug metabolizing enzymes throughout the endoplasmic reticulum is known to be heterogeneous and these "tags" could differ from the total endoplasmic reticulum (microsomes) in their enzyme make-up. Whether these enzymes are in the nuclear membrane, nucleoplasm, or as "tags" of endoplasmic reticulum, they represent activities in close proximity to potential target sites in the nucleus. The inhibition, induction, and activation characteristics of nuclear and microsomal enzymes were studied with the goal of selective manipulation of nuclear enzymes. The enzymes in the nuclear and microsomal fractions were found to differ' only in quantitative inducibility, and were identical in all other respects. Therefore, the selective manipulation of nuclear enzymes was not achieved. The induction of hepatic drug metabolizing enzymes is a measure of altered genetic expression in the liver. Inducers of drug metabolizing enzymes have also been shown to promote neoplasia in the liver. Therefore, studying the induction of such enzymes may lead to a further understanding of the mechanism of tumour promotion. Phenobarbital, 3-methylcholanthrene and pregnenolone-16α-carbonitrile produce three distinct induction responses. In the present study, spironolactone and trans-stiIbene oxide were shown to produce distinct induction responses, also. Spironolactone was shown to be a different inducer based on the protein band patterns observed following SDS-polyacrylamide gel electrophoresis of liver microsomes. trans-Stilbene oxide was found to produce a significantly different maximal level of AHH activity. The observation of five…

Subjects/Keywords: Carcinogens – pharmacokinetics; Enzyme Induction – drug effects; Carcinogenesis; Enzyme induction

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

APA (6^th Edition):

Gontovnick, L. S. (1981). Nuclear localization and induction of rat hepatic drug metabolizing enzymes. (Doctoral Dissertation). University of British Columbia. Retrieved from http://hdl.handle.net/2429/22783

Chicago Manual of Style (16^th Edition):

Gontovnick, Larry Stuart. “Nuclear localization and induction of rat hepatic drug metabolizing enzymes.” 1981. Doctoral Dissertation, University of British Columbia. Accessed January 18, 2021. http://hdl.handle.net/2429/22783.

MLA Handbook (7^th Edition):

Gontovnick, Larry Stuart. “Nuclear localization and induction of rat hepatic drug metabolizing enzymes.” 1981. Web. 18 Jan 2021.

Vancouver:

Gontovnick LS. Nuclear localization and induction of rat hepatic drug metabolizing enzymes. [Internet] [Doctoral dissertation]. University of British Columbia; 1981. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2429/22783.

Council of Science Editors:

Gontovnick LS. Nuclear localization and induction of rat hepatic drug metabolizing enzymes. [Doctoral Dissertation]. University of British Columbia; 1981. Available from: http://hdl.handle.net/2429/22783

King Abdullah University of Science and Technology

2. Martinez Banderas, Aldo. A Combined Chemical and Magneto-Mechanical Induction of Cancer Cell Death by the Use of Functionalized Magnetic Iron Nanowires.

Degree: 2016, King Abdullah University of Science and Technology

URL: http://hdl.handle.net/10754/606100

► Cancer prevails as one of the most devastating diseases being at the top of death causes for adults despite continuous development and innovation in cancer… (more)

▼ Cancer prevails as one of the most devastating diseases being at the top of death causes for adults despite continuous development and innovation in cancer therapy. Nanotechnology may be used to achieve therapeutic dosing, establish sustained-release drug profiles, and increase the half-life of drugs. In this context, magnetic nanowires (NWs) have shown a good biocompatibility and cellular internalization with a low cytotoxic effect. In this thesis, I induced cancer cell death by combining the chemotherapeutic effect of iron NWs functionalized with Doxorubicin (DOX) with mechanical disturbance under a low frequency alternating magnetic field. Two different agents, APTES and BSA, were separately used for coating NWs permitting further functionalization with DOX. Internalization was qualitatively and quantitatively assessed for both formulations by confocal reflection microscopy and inductively coupled plasma-mass spectrometry. From confocal reflection analysis, BSA formulations demonstrate to have a higher internalization degree and a broader distribution within the cells in comparison to APTES formulations. Both groups of functionalized NWs generated a comparable cytotoxic effect in MDA-MB-231 breast cancer cells in a DOX concentration-dependent manner, (~60% at the highest concentration tested) that was significantly different from the effect produced by the free DOX (~95% at the same concentration) and non-functionalized NWs formulations (~10% at the same NWs concentration). A synergistic cytotoxic effect is obtained when a low frequency magnetic field (1 mT, 10 Hz) is applied to cells treated with the two formulations that is again comparable (~70% at the highest concentration). Furthermore, the cytotoxic effect of both groups of coated NWs without the drug increased notoriously when the field is applied (~25% at the highest concentration tested). Here, a novel bimodal method for cancer cell destruction was developed by the conjugation of the magneto-mechanical properties of the iron NWs coupled with the chemotoxic effect of an anticancer drug. Moreover, it was demonstrated that iron nanowires possess an outstanding biocompatibility and showed high efficacy as drug delivery agents coupled to a high degree of cell internalization. Finally, the proposed method benefits from the low power fields applied during treatment. This poses much less safety risks and allows using cheaper and simpler equipment.

Subjects/Keywords: Magnetic Nanowires; Functionalization; Alternating magnetic field induction; drug delivery; cancer therapy; nanomedicine

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APA (6^th Edition):

Martinez Banderas, A. (2016). A Combined Chemical and Magneto-Mechanical Induction of Cancer Cell Death by the Use of Functionalized Magnetic Iron Nanowires. (Thesis). King Abdullah University of Science and Technology. Retrieved from http://hdl.handle.net/10754/606100

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):

Martinez Banderas, Aldo. “A Combined Chemical and Magneto-Mechanical Induction of Cancer Cell Death by the Use of Functionalized Magnetic Iron Nanowires.” 2016. Thesis, King Abdullah University of Science and Technology. Accessed January 18, 2021. http://hdl.handle.net/10754/606100.

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

MLA Handbook (7^th Edition):

Martinez Banderas, Aldo. “A Combined Chemical and Magneto-Mechanical Induction of Cancer Cell Death by the Use of Functionalized Magnetic Iron Nanowires.” 2016. Web. 18 Jan 2021.

Vancouver:

Martinez Banderas A. A Combined Chemical and Magneto-Mechanical Induction of Cancer Cell Death by the Use of Functionalized Magnetic Iron Nanowires. [Internet] [Thesis]. King Abdullah University of Science and Technology; 2016. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10754/606100.

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

Council of Science Editors:

Martinez Banderas A. A Combined Chemical and Magneto-Mechanical Induction of Cancer Cell Death by the Use of Functionalized Magnetic Iron Nanowires. [Thesis]. King Abdullah University of Science and Technology; 2016. Available from: http://hdl.handle.net/10754/606100

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

University of Toronto

3. Miller, Rebecca. The Expression and Regulation of CYP2D in a Monkey Model of Ethanol and Nicotine Exposure.

Degree: 2013, University of Toronto

URL: http://hdl.handle.net/1807/35642

►

CYP2D6 metabolizes a range of centrally acting drugs, neurotoxins, and endogenous neurochemicals. Higher levels of brain, but not liver, CYP2D6 have been identified in alcoholics… (more)

Subjects/Keywords: CYP2D6; Nicotine; Ethanol; African green monkey; Induction; Brain; Liver; Smokers; Alcoholics; Parkinson's disease; Personality; Brain drug metabolism; 0419

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

APA (6^th Edition):

Miller, R. (2013). The Expression and Regulation of CYP2D in a Monkey Model of Ethanol and Nicotine Exposure. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/35642

Chicago Manual of Style (16^th Edition):

Miller, Rebecca. “The Expression and Regulation of CYP2D in a Monkey Model of Ethanol and Nicotine Exposure.” 2013. Masters Thesis, University of Toronto. Accessed January 18, 2021. http://hdl.handle.net/1807/35642.

MLA Handbook (7^th Edition):

Miller, Rebecca. “The Expression and Regulation of CYP2D in a Monkey Model of Ethanol and Nicotine Exposure.” 2013. Web. 18 Jan 2021.

Vancouver:

Miller R. The Expression and Regulation of CYP2D in a Monkey Model of Ethanol and Nicotine Exposure. [Internet] [Masters thesis]. University of Toronto; 2013. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1807/35642.

Council of Science Editors:

Miller R. The Expression and Regulation of CYP2D in a Monkey Model of Ethanol and Nicotine Exposure. [Masters Thesis]. University of Toronto; 2013. Available from: http://hdl.handle.net/1807/35642

University of Cincinnati

4. Li, Fang. Investigation of BAS 100, a Naturally Occurring CYP3A Inhibitor, as a Bioavailability Boosting Agent.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2007, University of Cincinnati

URL: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1195794592

► Numerous drug agents exhibit low and erratic oral bioavailability. Drug metabolizing enzymes (DMEs) such as cytochrome P450 3A4 (CYP3A4) and efflux transporters (DTs) such as… (more)

▼ Numerous drug agents exhibit low and erratic oral bioavailability. Drug metabolizing enzymes (DMEs) such as cytochrome P450 3A4 (CYP3A4) and efflux transporters (DTs) such as P-gp, BCRP and MRP2 are major barriers that restrict oral drug bioavailability. Inhibition of CYP3A4 by ritonavir is a clinically proven strategy for enhancing oral bioavailability. Based on the observation that grapefruit juice (GFJ) consumption inhibits CYP3A4 activity and enhances the systemic exposure of CYP3A4 substrates, extensive efforts have been made to isolate the CYP3A4 inhibitory components of GFJ. Accordingly, BAS 100, a spiro-ortho-ester, isolated by Bioavailability Systems Inc, is a promising CYP3A4 inhibitor. In preliminary studies BAS 100 was observed to considerably enhance the pharmacokinetics of saquinavir, an antiretroviral drug metabolized by CYP3A4. This study was undertaken to gain mechanistic insights into BAS 100 as a bioavailability enhancer. First, employing human liver microsomal incubations we observed that BAS 100 was a potent competitive inhibitor of CYP3A4 with an IC₅₀ to be 37.0 nM. Comparatively, ritonavir, a well-known CYP3A4 inhibitor, had an IC₅₀ of 43.0 nM. In addition, BAS 100 demonstrated mechanism-based CYP3A4 inhibition, with the K_I and K_inact for BAS 100 and ritonavir being 0.37 μM and 0.73 min^-1 and 0.36 μM and 0.25 min^-1, respectively. We then evaluated the induction potential of BAS 100 on hepatic CYP3A4 expression and activity after long-term exposure. Although, BAS 100 and ritonavir increased CYP3A4 transcription, they markedly inhibited the CYP3A4 activity. Using MDCK cell lines stably transfected with MDR1, which encodes P-gp, bcrp1 or MRP2 genes we further compared BAS 100 and ritonavir for their ability to inhibit drug transport. Finally, we conducted a pilot “proof-of-concept” <i>in vivo</i> study to investigate the effects of BAS 100 on the bioavailability of docetaxel, an anti-cancer agent metabolized by CYP3A4 and exhibiting extremely poor oral bioavailability. In FVB mice BAS 100 and ritonavir markedly increased the exposure of docetaxel by 29- and 28-fold, respectively. Taken together, our study indicates that BAS 100 is very similar to ritonavir in its effect on inhibiting CYP3A4 activity and has the potential to enhance the systemic exposure to drugs with low oral bioavailability Advisors/Committee Members: Desai, Dr. Pankaj (Advisor).

Subjects/Keywords: Health Sciences, Pharmacology; CYP3A; Inhibition; Induction; Bioavailability; Drug transporters

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

APA (6^th Edition):

Li, F. (2007). Investigation of BAS 100, a Naturally Occurring CYP3A Inhibitor, as a Bioavailability Boosting Agent. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1195794592

Chicago Manual of Style (16^th Edition):

Li, Fang. “Investigation of BAS 100, a Naturally Occurring CYP3A Inhibitor, as a Bioavailability Boosting Agent.” 2007. Doctoral Dissertation, University of Cincinnati. Accessed January 18, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1195794592.

MLA Handbook (7^th Edition):

Li, Fang. “Investigation of BAS 100, a Naturally Occurring CYP3A Inhibitor, as a Bioavailability Boosting Agent.” 2007. Web. 18 Jan 2021.

Vancouver:

Li F. Investigation of BAS 100, a Naturally Occurring CYP3A Inhibitor, as a Bioavailability Boosting Agent. [Internet] [Doctoral dissertation]. University of Cincinnati; 2007. [cited 2021 Jan 18]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1195794592.

Council of Science Editors:

Li F. Investigation of BAS 100, a Naturally Occurring CYP3A Inhibitor, as a Bioavailability Boosting Agent. [Doctoral Dissertation]. University of Cincinnati; 2007. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1195794592

5. Araújo, Ana Patrícia Loureiro Machado Gomes de. O papel da glicoproteína-P nas interações fármaco-fármaco.

Degree: 2015, Universidade Fernando Pessoa

URL: http://www.rcaap.pt/detail.jsp?id=oai:bdigital.ufp.pt:10284/5156

►

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

A glicoproteína-p (gp-P) foi… (more)

▼

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

A glicoproteína-p (gp-P) foi descrita pela primeira vez em 1976 como uma glicoproteína de superfície presente na membrana citoplasmática. Esta é uma bomba de efluxo que pertence à família de transportadores ABC e que participa no fenómeno de resistência a múltiplos fármacos. Encontra-se amplamente distribuída nos tecidos e participa em variadas funções fisiológicas importantes. É expressa nos pontos de entrada dos xenobióticos (trato gastrointestinal, fígado, rins, cérebro, placenta) e consegue efetuar o transporte destes para o exterior das células. É também expressa em barreiras hemato-teciduais e em células tumorais, impedindo a entrada de substâncias nestes tecidos graças ao seu transporte para fora das células. Desempenha um papel crucial na absorção, distribuição, metabolização e excreção de muitos fármacos no organismo. Atua na proteção dos tecidos contra xenobióticos tóxicos e metabolitos endógenos, através da excreção destes compostos para o lúmen intestinal, bílis, urina e promovendo também a sua expulsão do sistema nervoso central. As interações farmacológicas ocorrem quando os efeitos de um fármaco são alterados pela presença de outro fármaco, alimento, ou outro agente químico. Neste trabalho são discutidas algumas das interações fármaco-fármaco mais importantes envolvendo a gp- P. A co-adminstração de fármacos que são indutores ou inibidores da gp-P pode originar uma interação farmacológica. Quando os fármacos atuam como inibidores de gp-P originam um aumento dos seus substratos a nível intracelular, graças ao decréscimo do transporte de efluxo de fármacos. Para além dos fármacos que têm a capacidade de inibir a gp-P, outras moléculas como os surfactantes (tween-20) usados na indústria farmacêutica podem também inibi-la. A gp-P é ainda considerada de fácil indução quer in vivo quer in vitro, sendo conhecidos vários tipos de indutores. Estes atuam aumentando o transporte de efluxo, diminuindo assim a biodisponibilidade dos fármacos que são transportados por esta proteína. Quanto maior o número de fármacos co-administrados maior é a probabilidade de ocorrer interação farmacológica. The p-glycoprotein (P-gp) was first described in 1976 as a surface glycoprotein present in the cytoplasmic membrane. It is an efflux pump that belongs to the ABC transporter family and is involved in multidrug resistance phenomenon. It is widely distributed in tissues and participate in a variety of important physiological functions. Since it is expressed in the entry points of xenobiotics (gastrointestinal tract, liver, kidneys, brain and placenta) it can make the transportation of these substances outside of the cells. It is also expressed in the blood-tissue barriers and tumour cells, preventing the entry of xenobiotics in these tissues. P-gp plays a crucial role in the absorption, distribution,…

Advisors/Committee Members: Catarino, Rita, Pimenta, Adriana.

Subjects/Keywords: Glicoproteina-P; Interações fármaco-fármaco; Indução; Inibição transportador de múltiplos fármacos; Bombas de efluxo; P-Glycoprotein; Drug-Drug interactions; Inhibition; Induction; Multidrug transporter; Efflux pumps

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

APA (6^th Edition):

Araújo, A. P. L. M. G. d. (2015). O papel da glicoproteína-P nas interações fármaco-fármaco. (Thesis). Universidade Fernando Pessoa. Retrieved from http://www.rcaap.pt/detail.jsp?id=oai:bdigital.ufp.pt:10284/5156

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):

Araújo, Ana Patrícia Loureiro Machado Gomes de. “O papel da glicoproteína-P nas interações fármaco-fármaco.” 2015. Thesis, Universidade Fernando Pessoa. Accessed January 18, 2021. http://www.rcaap.pt/detail.jsp?id=oai:bdigital.ufp.pt:10284/5156.

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

MLA Handbook (7^th Edition):

Araújo, Ana Patrícia Loureiro Machado Gomes de. “O papel da glicoproteína-P nas interações fármaco-fármaco.” 2015. Web. 18 Jan 2021.

Vancouver:

Araújo APLMGd. O papel da glicoproteína-P nas interações fármaco-fármaco. [Internet] [Thesis]. Universidade Fernando Pessoa; 2015. [cited 2021 Jan 18]. Available from: http://www.rcaap.pt/detail.jsp?id=oai:bdigital.ufp.pt:10284/5156.

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

Council of Science Editors:

Araújo APLMGd. O papel da glicoproteína-P nas interações fármaco-fármaco. [Thesis]. Universidade Fernando Pessoa; 2015. Available from: http://www.rcaap.pt/detail.jsp?id=oai:bdigital.ufp.pt:10284/5156

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

NSYSU

6. Yon, Chuen-huei. Applications of Data Mining on Drug Safety: Predicting Proper Dosage of Vancomycin for Patients with Renal Insufficiency and Impairment.

Degree: Master, Information Management, 2004, NSYSU

URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0824104-162427

► Abstract Drug misuses result in medical resource wastes and significant society costs. Due to the narrow therapeutic range of vancomycin, appropriate vancomycin dosage is difficult… (more)

▼ Abstract Drug misuses result in medical resource wastes and significant society costs. Due to the narrow therapeutic range of vancomycin, appropriate vancomycin dosage is difficult to determine. When inappropriate dosage is used, such side effects as poisoning reaction or drug resistance may occur. Clinically, medical professionals adjust drug protocols of vancomycin based on the Therapeutic Drug Monitoring (TDM) results. TDM is usually defined as the clinical use of drug blood concentration measurements as an aid in dosage finding and adjustment. However, TDM cannot be applied to first-time treatments and, in case, dosage decisions need to reply on medical professionalsâ clinical experiences and judgments. Data mining has been applied in various medical and healthcare applications. In this study, we will employ a decision-tree induction (specifically, C4.5) and a backpropagation neural network technique for predicting the appropriateness of vancomycin usage for patients with renal insufficiency and impairment. In addition, we will evaluate whether the use of the boosting and bagging algorithms will improve predictive accuracy. Our empirical evaluation results suggest that use of the boosting and bagging algorithms could improve predictive accuracy. Specifically, use of C4.5 in conjunction with the AdaBoost algorithm achieves an overall accuracy of 79.65%, which significantly improves that of the existing practice, recording an accuracy rate at 41.38%. With respect to the appropriateness category (âYâ) and the inappropriateness category (âNâ), C4.5 in conjunction with the AdaBoost algorithm can achieve a recall rate at 78.75% and 80.25%, respectively. Hence, the incorporation of data mining techniques to decision support would enhance the drug safety, which in turn, would improve patient safety and reduce subsequent medical resource wastes. Advisors/Committee Members: Chih-Ping Wei (committee member), Hsin-Hui Lin (chair), Fan-Hui Lin (chair), Tsang-Hsiang Cheng (committee member).

Subjects/Keywords: Data Mining; AdaBoost; Drug Safety; Bagging; Backpropagation Network; Classification Analysis; Decision Tree Induction

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

APA (6^th Edition):

Yon, C. (2004). Applications of Data Mining on Drug Safety: Predicting Proper Dosage of Vancomycin for Patients with Renal Insufficiency and Impairment. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0824104-162427

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):

Yon, Chuen-huei. “Applications of Data Mining on Drug Safety: Predicting Proper Dosage of Vancomycin for Patients with Renal Insufficiency and Impairment.” 2004. Thesis, NSYSU. Accessed January 18, 2021. http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0824104-162427.

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

MLA Handbook (7^th Edition):

Yon, Chuen-huei. “Applications of Data Mining on Drug Safety: Predicting Proper Dosage of Vancomycin for Patients with Renal Insufficiency and Impairment.” 2004. Web. 18 Jan 2021.

Vancouver:

Yon C. Applications of Data Mining on Drug Safety: Predicting Proper Dosage of Vancomycin for Patients with Renal Insufficiency and Impairment. [Internet] [Thesis]. NSYSU; 2004. [cited 2021 Jan 18]. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0824104-162427.

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

Council of Science Editors:

Yon C. Applications of Data Mining on Drug Safety: Predicting Proper Dosage of Vancomycin for Patients with Renal Insufficiency and Impairment. [Thesis]. NSYSU; 2004. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0824104-162427

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

7. Pinheiro Júnior, Edilson Diógenes. Experiência do Serviço de Hematologia do Hospital das Clínicas da FMUSP com leucemia linfóide aguda do adulto: avaliação clínica, laboratorial e dos protocolos de tratamento.

Degree: Mestrado, Hematologia, 2008, University of São Paulo

URL: http://www.teses.usp.br/teses/disponiveis/5/5136/tde-24062008-122745/ ;

► A leucemia linfóide aguda nos adultos apresenta prognóstico reservado. Os objetivos deste estudo são descrição e análise de parâmetros clínicos, laboratoriais e fatores prognósticos em… (more)

▼ A leucemia linfóide aguda nos adultos apresenta prognóstico reservado. Os objetivos deste estudo são descrição e análise de parâmetros clínicos, laboratoriais e fatores prognósticos em 102 pacientes tratados com diferentes protocolos de quimioterapia no período de 1990 a 2005, no Serviço de Hematologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Em estudo de coorte retrospectivo, com exclusão de LLA subtipo L3 (FAB) ou B-IV (EGIL), foram analisadas a taxa de remissão completa (RC), sobrevida global (SG) e sobrevida livre de doença (SLD) para a população geral e para os dois principais protocolos de tratamento. A análise estatística foi feita pelo programa SPSS 10.0. Associação entre variáveis, fatores prognósticos e resposta foram observados através do teste ?2 de Person. Curvas de SG e SLD foram construídas pelo método de Kaplan-Meier e as diferenças analisadas pelo teste de log-rank. A idade média foi de 30,6 anos (12 a 82 anos) e predominou o sexo masculino (55,9%). Ao diagnóstico, os achados clínicos foram: fadiga (58,2%), esplenomegalia (59,7%), hepatomegalia (54,6%), linfadenopatia (52,6), febre (38,8%), dor óssea(28,6%), sangramento (27,5%) e cefaléia (15,3%). Envolvimento do sistema nervoso central (SNC) foi detectado em 11 (11,8%) pacientes, enquanto envolvimento testicular acometeu um paciente. O valor médio de hemoglobina, leucócitos e plaquetas foram 8,5g/dl, 84.341/mm3 e 76.275/mm3, respectivamente. 98,7% dos pacientes apresentaram linfoblastos no sangue periférico. A classificação FAB foi igualmente observada entre os tipos L1 e L2. As LLA B e T foram observadas em 69,7% e 30,2%, respectivamente. O cariótipo foi realizado em 40 pacientes, e t (9;22) foi identificada em 20% (8/40) dos casos. Os pacientes foram tratados com quatro diferentes protocolos: BFM 86 modificado (BFM 86M) em 47,15% (48/102), Linker et al em 39,2% (40/102), Lister et al em 5,9% (6/102) e CHOP em 7,8% (8/102). Na análise para a população geral, na fase de indução, 70,6% (65/92) dos pacientes entraram em RC. Idade inferior a 18 anos e ausência de infiltração de SNC foram fatores preditores positivos de resposta em análise multivariada (p=0,03). Com mediana de seguimento de 49 meses, observamos taxa de 30,5% e 27% para SG e SLD em 4 anos. Ausência de sangramento e hepatomegalia, ao diagnóstico, e idade < 35 anos estiveram associados à maior SG através de análise multivariada (p=0,01). Os dois protocolos com maior número de pacientes, apresentaram distribuição semelhante de parâmetros clínicos e laboratoriais, a exceção da variável FAB. RC foi obtida em 76,7% e 63,9% dos pacientes tratados respectivamente com os protocolos BFM 86M e Linker (p=0,21). A SG foi de 49,5% com o BFM 86M em 4 anos Vs 16% com o protocolo Linker (p=0,004). Observou-se que o protocolo BFM86M teve melhor SG para pacientes com idade <35 anos (p=0,01), sem sangramento e hepatomegalia ao diagnóstico (p=0,03 e p=0,01) e sem leucocitose (B <30.000mm3 e T <100.000mm) (p=0,04); enquanto que pacientes com LLA T tratados com o… Advisors/Committee Members: Velloso, Elvira Deolinda Rodrigues Pereira.

Subjects/Keywords: Acute lymphocytic; Acute lymphocytic leukemia/drug therapy; Adult; Adulto; Indução de remissão; Leucemia linfocítica aguda/quimioterapia; Leucemia linfocítica aguda/terapia; Leukemia/therapy; Prognosis; Prognóstico; Remission induction; Sobrevida; Survivorship (public health)

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

APA (6^th Edition):

Pinheiro Júnior, E. D. (2008). Experiência do Serviço de Hematologia do Hospital das Clínicas da FMUSP com leucemia linfóide aguda do adulto: avaliação clínica, laboratorial e dos protocolos de tratamento. (Masters Thesis). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/5/5136/tde-24062008-122745/ ;

Chicago Manual of Style (16^th Edition):

Pinheiro Júnior, Edilson Diógenes. “Experiência do Serviço de Hematologia do Hospital das Clínicas da FMUSP com leucemia linfóide aguda do adulto: avaliação clínica, laboratorial e dos protocolos de tratamento.” 2008. Masters Thesis, University of São Paulo. Accessed January 18, 2021. http://www.teses.usp.br/teses/disponiveis/5/5136/tde-24062008-122745/ ;.

MLA Handbook (7^th Edition):

Pinheiro Júnior, Edilson Diógenes. “Experiência do Serviço de Hematologia do Hospital das Clínicas da FMUSP com leucemia linfóide aguda do adulto: avaliação clínica, laboratorial e dos protocolos de tratamento.” 2008. Web. 18 Jan 2021.

Vancouver:

Pinheiro Júnior ED. Experiência do Serviço de Hematologia do Hospital das Clínicas da FMUSP com leucemia linfóide aguda do adulto: avaliação clínica, laboratorial e dos protocolos de tratamento. [Internet] [Masters thesis]. University of São Paulo; 2008. [cited 2021 Jan 18]. Available from: http://www.teses.usp.br/teses/disponiveis/5/5136/tde-24062008-122745/ ;.

Council of Science Editors:

Pinheiro Júnior ED. Experiência do Serviço de Hematologia do Hospital das Clínicas da FMUSP com leucemia linfóide aguda do adulto: avaliação clínica, laboratorial e dos protocolos de tratamento. [Masters Thesis]. University of São Paulo; 2008. Available from: http://www.teses.usp.br/teses/disponiveis/5/5136/tde-24062008-122745/ ;

University of Waterloo

8. Sadatmousavi, Parisa. Peptide-Mediated Anticancer Drug Delivery.

Degree: 2009, University of Waterloo

URL: http://hdl.handle.net/10012/4577

► An ideal drug delivery system should contain an appropriate therapeutic agent and biocompatible carrier. In this study, we investigated the ability of the all-complementary self-assembling… (more)

Subjects/Keywords: All-complimentary self-assembling peptide; hydrophobic anticancer drug; drug encapsulation; critical assembly concentration; Cytotoxicity; Apoptosis induction

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

APA (6^th Edition):

Sadatmousavi, P. (2009). Peptide-Mediated Anticancer Drug Delivery. (Thesis). University of Waterloo. Retrieved from http://hdl.handle.net/10012/4577

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):

Sadatmousavi, Parisa. “Peptide-Mediated Anticancer Drug Delivery.” 2009. Thesis, University of Waterloo. Accessed January 18, 2021. http://hdl.handle.net/10012/4577.

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

MLA Handbook (7^th Edition):

Sadatmousavi, Parisa. “Peptide-Mediated Anticancer Drug Delivery.” 2009. Web. 18 Jan 2021.

Vancouver:

Sadatmousavi P. Peptide-Mediated Anticancer Drug Delivery. [Internet] [Thesis]. University of Waterloo; 2009. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10012/4577.

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

Council of Science Editors:

Sadatmousavi P. Peptide-Mediated Anticancer Drug Delivery. [Thesis]. University of Waterloo; 2009. Available from: http://hdl.handle.net/10012/4577

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

Penn State University

9. De Keyser, Joshua Gordon. ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9350

► The human constitutive androstane receptor (CAR) regulates the expression of genes involved in xenobiotic metabolism in the liver. The CAR gene utilizes multiple alternative splicing… (more)

▼ The human constitutive androstane receptor (CAR) regulates the expression of genes involved in xenobiotic metabolism in the liver. The CAR gene utilizes multiple alternative splicing events during pre-mRNA processing, thereby increasing the CAR transcriptome. The work presented in this dissertation focuses on the functional analysis of a prominent human CAR variant, CAR2 that possesses a 4- amino acid insertion in the ligand binding domain. Previous investigations led us to hypothesize that the CAR2 variant is a ligand-activated receptor and possesses a unique ligand binding profile giving rise to novel biological function. We now demonstrate that CAR2 constitutes approximately one-third and one-half of the total CAR transcriptome in human hepatocytes and small intestine, respectively. Further, we identify the common plasticizers, di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP) as highly potent and uniquely selective agonists of CAR2. Results from reporter transactivation assays reveal that DEHP and DiNP activate CAR2 at low nanomolar concentrations. In addition, comparative genomic analysis show that the typical mouse, rat and marmoset models of toxicity can not accurately profile potential human toxicity due to these species inability to generate a CAR2-like transcript. It is also demonstrated that CAR2 possesses an altered ligand pocket that allows for the highly potent and specific activation of the variant by DEHP and DiNP. Further studies show that CAR1 and CAR3 share similar ligand activation profiles; whereas CAR2 responds to most CAR1 and CAR3 ligands as well as a unique subset of chemicals. Finally, it is now shown that meclizine, a human CAR1 inverse-agonist, is a specific agonist of CAR2. A meclizine derived pharmacophore was utilized in a ligand-based virtual screening and identified two novel CAR2 agonists from the NCI chemical database. The results of this dissertation will aid in the development of better models of human CAR activation, give a more complete understanding of the interaction of CAR with xenobiotics, yield novel insight into potential mechanisms of phthalate toxicity and provide the foundation for future studies into the physiologic functions of alternatively spliced variants of CAR. Advisors/Committee Members: Curtis John Omiecinski, Dissertation Advisor/Co-Advisor, Curtis John Omiecinski, Committee Chair/Co-Chair, Reka Z Albert, Committee Member, Adam Bleier Glick, Committee Member, John Patrick Vanden Heuvel, Committee Member.

Subjects/Keywords: phthalates; alternative splicing; constitutive androstane receptor; drug and xenobiotic metabolism; meclizine; nuclear receptors; gene induction

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

APA (6^th Edition):

De Keyser, J. G. (2009). ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9350

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):

De Keyser, Joshua Gordon. “ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY .” 2009. Thesis, Penn State University. Accessed January 18, 2021. https://submit-etda.libraries.psu.edu/catalog/9350.

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

MLA Handbook (7^th Edition):

De Keyser, Joshua Gordon. “ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY .” 2009. Web. 18 Jan 2021.

Vancouver:

De Keyser JG. ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Jan 18]. Available from: https://submit-etda.libraries.psu.edu/catalog/9350.

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

Council of Science Editors:

De Keyser JG. ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/9350

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

North Carolina State University

10. Jackson, Jonathan Patrick. The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases.

Degree: PhD, Toxicology, 2007, North Carolina State University

URL: http://www.lib.ncsu.edu/resolver/1840.16/4828

► The CYP2C subfamily of cytochrome P450 monoxygenases (P450) is responsible for the metabolism of approximately 20% of therapeutic drugs. Recently, phenytoin has been reported to… (more)

▼ The CYP2C subfamily of cytochrome P450 monoxygenases (P450) is responsible for the metabolism of approximately 20% of therapeutic drugs. Recently, phenytoin has been reported to induce the expression of the human genes CYP2B6, CYP3A4, and CYP2C8. Cytochrome P450 expression is often induced by prior exposure to xenobiotics often resulting in drug-drug interactions. Induction of the human CYP2C enzymes by xenobiotics occurs at the transcriptional level and is reported to involve the constitutive androstane receptor (CAR) and/or the pregnane X receptor (PXR). However, the molecular mechanisms regulating drug induction of the murine CYP2C enzymes remain unclear. The mouse is an excellent model system to investigate CYP2C drug induced transcription due to the availability of nuclear receptor knockout mice. Herein, we report the identification of two phenobarbital and phenytoin inducible murine CYP2C genes, Cyp2c29 and Cyp2c37. Quantitative RT-PCR demonstrates that hepatic CYP2C29 and CYP2C37 mRNA is induced by phenobarbital and phenytoin. Additionally, immunoblots indicated that phenytoin induced hepatic CYP2C29 and CYP2C37 protein. We utilized in vivo gene reporter assays of the Cyp2c29 promoter to delineate the phenytoin-response activity to a phenytoin responsive module (PHREM) located -1371 bp upstream of the Cyp2c29 translation start site. Similarly, using in vitro gene reporter assays of the Cyp2c37 promoter, we identified a single functional CAR-RE located -2791 bp upstream of translation start site of Cyp2c37. Mutagenesis studies demonstrated that these sites are essential for CAR transactivation of their respective gene promoters in HepG2 cells. Using quantitative RT-PCR, we demonstrated that induction of CYP2B10 mRNA by phenytoin was completely abolished in CAR-null mice, but only moderately reduced in PXR-null mice. Similarly, phenytoin induction of CYP2C29 and CYP2C37 mRNA was severely reduced in CAR-null mice and only modestly reduced in PXR-null mice. Taken together, these results indicate that the induction of Cyp2b10, Cyp2c29, and Cyp2c37 by phenytoin is predominately regulated by mCAR. However, induction of CYP3A11 mRNA was only partially decreased in either null mice strain. Studies have demonstrated that CYP3A11 mRNA is induced by CAR and PXR agonists, thus our results also indicate that phenytoin acts as an agonist of both CAR and PXR. Advisors/Committee Members: Joyce A Goldstein, Ph.D., Committee Co-Chair (advisor), Randy Rose, Ph.D., Committee Co-Chair (advisor), Masahiko Negishi, Ph.D., Committee Member (advisor), Andrew Wallace, Ph.D., Committee Member (advisor), Ernest Hodgson, Ph.D., Committee Member (advisor).

Subjects/Keywords: Cyp2c37; Cyp2c29; Nuclear Receptors; Pregnane X Receptor; Constitutive Androstane Receptor; Phenytoin; Phenobarbital; Drug Induction

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

APA (6^th Edition):

Jackson, J. P. (2007). The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases. (Doctoral Dissertation). North Carolina State University. Retrieved from http://www.lib.ncsu.edu/resolver/1840.16/4828

Chicago Manual of Style (16^th Edition):

Jackson, Jonathan Patrick. “The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases.” 2007. Doctoral Dissertation, North Carolina State University. Accessed January 18, 2021. http://www.lib.ncsu.edu/resolver/1840.16/4828.

MLA Handbook (7^th Edition):

Jackson, Jonathan Patrick. “The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases.” 2007. Web. 18 Jan 2021.

Vancouver:

Jackson JP. The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases. [Internet] [Doctoral dissertation]. North Carolina State University; 2007. [cited 2021 Jan 18]. Available from: http://www.lib.ncsu.edu/resolver/1840.16/4828.

Council of Science Editors:

Jackson JP. The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases. [Doctoral Dissertation]. North Carolina State University; 2007. Available from: http://www.lib.ncsu.edu/resolver/1840.16/4828

University of Montana

11. mcgrath, kelly j. NATURAL PRODUCT INDUCTION IN PENCILLIUM AND HUMAN CASPASE CRYSTALLOGRAPHY.

Degree: MS, 2019, University of Montana

URL: https://scholarworks.umt.edu/etd/11313

Subjects/Keywords: Natural products; drug design; protein crystallography; induction; extremophile; caspase; Biochemical Phenomena, Metabolism, and Nutrition; Chemical and Pharmacologic Phenomena

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

APA (6^th Edition):

mcgrath, k. j. (2019). NATURAL PRODUCT INDUCTION IN PENCILLIUM AND HUMAN CASPASE CRYSTALLOGRAPHY. (Masters Thesis). University of Montana. Retrieved from https://scholarworks.umt.edu/etd/11313

Chicago Manual of Style (16^th Edition):

mcgrath, kelly j. “NATURAL PRODUCT INDUCTION IN PENCILLIUM AND HUMAN CASPASE CRYSTALLOGRAPHY.” 2019. Masters Thesis, University of Montana. Accessed January 18, 2021. https://scholarworks.umt.edu/etd/11313.

MLA Handbook (7^th Edition):

mcgrath, kelly j. “NATURAL PRODUCT INDUCTION IN PENCILLIUM AND HUMAN CASPASE CRYSTALLOGRAPHY.” 2019. Web. 18 Jan 2021.

Vancouver:

mcgrath kj. NATURAL PRODUCT INDUCTION IN PENCILLIUM AND HUMAN CASPASE CRYSTALLOGRAPHY. [Internet] [Masters thesis]. University of Montana; 2019. [cited 2021 Jan 18]. Available from: https://scholarworks.umt.edu/etd/11313.

Council of Science Editors:

mcgrath kj. NATURAL PRODUCT INDUCTION IN PENCILLIUM AND HUMAN CASPASE CRYSTALLOGRAPHY. [Masters Thesis]. University of Montana; 2019. Available from: https://scholarworks.umt.edu/etd/11313

University of Cincinnati

12. Hariparsad, Niresh. Hepatic and Extra-Hepatic Induction of Drug Metabolizing Enzymes and Drug Transporters by Antiretrovirals, in the Presence and Absence of Viral Infection.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2006, University of Cincinnati

URL: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1153244440

► Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) are important antiretroviral drugs (ARVs) included in the currently used highly active antiretroviral therapy (HAART) regimen.… (more)

▼ Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) are important antiretroviral drugs (ARVs) included in the currently used highly active antiretroviral therapy (HAART) regimen. While these agents have significantly improved the morbidity and mortality associated with HIV/AIDS, their clinical use remains fraught with numerous drug-drug interactions (DDIs) including induction of drug clearance pathways. This study represents an attempt to better understand the impact of these agents on key drug-metabolizing enzymes and drug transporters (DMTs) in hepatic and extra-hepatic tissues. In preliminary studies we observed that NNRTI efavirenz, and PIs, nelfinavir and ritonavir, activate the pregnane-X receptor (PXR), a key transcriptional regulator of DMTs. Based on this observation and other published reports, we hypothesized that these agents induce hepatic and extra-hepatic (intestinal and CD4+ T-cells) DMTs, and that the magnitude of induction is modulated by disease state. In Aim 1, employing primary human hepatocytes and LS174T colon carcinoma cell line, a clinically relevant model for intestinal drug metabolism studies, we observed that these drugs have a profound effect on several DMTs. Our studies revealed that efavirenz is potent inducer of CYP3A4, whereas the PIs increase CYP3A4 mRNA levels without a correlative increase in CYP3A4 activity. The three drugs also induced CYP2B6, UGT1A1 and UGT1A6, but only nelfinavir induced UGT2B7. Both PIs markedly induced P-gp. In Aim 2, we evaluated the effect of these drugs on expression and activity of DMTs in CD4+ T-cells. While all three ARVs produced significant increases in the P-gp function in CD4+ T-cells, nelfinavir was the most potent P-gp inducer. In the third Specific Aim, we observed that exposure of nelfinavir-treated CD4+ T-cells to infectious-HIV decreased P-gp activity which corresponded with a reduction in hPXR expression levels. A comparison of the effects on exposed-infected and exposed-uninfected cells revealed a significant decrease of P-gp activity in nelfinavir-treated exposed-infected cells, but an increase in the exposed-uninfected cells. The expression of hPXR was lower in nelfinavir-treated exposed-infected cells than exposed-uninfected cells. Taken together, our studies have provided novel insights into the factors that may increase the potential for drug-drug interactions and alter the intracellular pharmacology of important ARVs. Advisors/Committee Members: Desai, Dr. Pankaj (Advisor).

Subjects/Keywords: Induction; Hepatic and extra-hepatic; In vitro; Efavirenz, ritonavir, nelfinavir; Phase I and phase II drug metabolizing enzymes

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

APA (6^th Edition):

Hariparsad, N. (2006). Hepatic and Extra-Hepatic Induction of Drug Metabolizing Enzymes and Drug Transporters by Antiretrovirals, in the Presence and Absence of Viral Infection. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1153244440

Chicago Manual of Style (16^th Edition):

Hariparsad, Niresh. “Hepatic and Extra-Hepatic Induction of Drug Metabolizing Enzymes and Drug Transporters by Antiretrovirals, in the Presence and Absence of Viral Infection.” 2006. Doctoral Dissertation, University of Cincinnati. Accessed January 18, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1153244440.

MLA Handbook (7^th Edition):

Hariparsad, Niresh. “Hepatic and Extra-Hepatic Induction of Drug Metabolizing Enzymes and Drug Transporters by Antiretrovirals, in the Presence and Absence of Viral Infection.” 2006. Web. 18 Jan 2021.

Vancouver:

Hariparsad N. Hepatic and Extra-Hepatic Induction of Drug Metabolizing Enzymes and Drug Transporters by Antiretrovirals, in the Presence and Absence of Viral Infection. [Internet] [Doctoral dissertation]. University of Cincinnati; 2006. [cited 2021 Jan 18]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1153244440.

Council of Science Editors:

Hariparsad N. Hepatic and Extra-Hepatic Induction of Drug Metabolizing Enzymes and Drug Transporters by Antiretrovirals, in the Presence and Absence of Viral Infection. [Doctoral Dissertation]. University of Cincinnati; 2006. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1153244440

University of Manchester

13. Ghosh, Arunabha. Improving Diagnosis and Treatment Outcomes in Mucopolysaccharidoses.

Degree: 2018, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317761

► Mucopolysaccharidoses (MPS) are a heterogenous group of disorders caused by inherited deficiencies of enzymes involved in glycosaminoglycan degradation. Two such disorders, MPS I and MPS… (more)

▼ Mucopolysaccharidoses (MPS) are a heterogenous group of disorders caused by inherited deficiencies of enzymes involved in glycosaminoglycan degradation. Two such disorders, MPS I and MPS III, present distinct treatment challenges. In MPS I, significant areas of unmet need remain despite the existence of two therapies: enzyme replacement therapy (ERT) and haematopoietic stem cell transplantation (HSCT), the latter being the treatment choice in severe MPS I (Hurler syndrome). Several strategies to optimise diagnosis and treatment are considered: (1) the safety and utility of combined ERT and HSCT, a frequently used, though not universal, treatment approach; (2) mitigation of the antibody response to ERT, which may negatively impact treatment efficacy; (3) the development of genotype-phenotype relationships that would be relevant for the implementation of newborn screening, and could enable earlier initiation of therapy and improve outcomes. MPS III is a predominantly neurological disease with no existing treatment. The efficacy of genistein aglycone, a potential substrate reduction therapy, was investigated in MPS III patients. In a retrospective review of 81 MPS I patients who received peri-transplant ERT, overall survival was 88% and engrafted survival was 81% (median follow-up 46 months). Improvement in cardiopulmonary disease status during ERT enabled selected individuals to tolerate full intensity conditioning. An open-label study of prophylactic immune tolerance induction using methotrexate in three MPS I Hurler individuals found that one or three weeks of oral methotrexate did not prevent high titre anti-drug antibody responses. However, in an MPS I mouse model, two courses of an anti-CD4 monoclonal antibody prevented antibody responses to ERT in seven out of eight mice (87.5%). Analysis of genotypes and phenotypic severity in a cohort of 286 MPS I patients identified 63 IDUA variants, of which 20 were novel, and associations with phenotypic severity were assigned for all but six. A total of 37 variants were only identified in a single individual or family, but this accounted for only 13% of individuals. In 57% of individuals, both alleles were one of nine common variants. A double-blinded, randomised, placebo-controlled clinical trial of high dose genistein aglycone (160mg/kg/day) in MPS III found that 12 months of genistein did not result in a significantly lower concentration of cerebrospinal fluid heparan sulfate than placebo (p=0.26), and the size of reduction (5.5%) was not clinically meaningful. No deviation from natural history in neuropsychological measures was observed. These findings suggest potential approaches to improving diagnosis and treatment. Combined ERT and HSCT in MPS I has clinical utility for selected high risk individuals, though patients are known to develop anti-drug antibodies. These could be mitigated by immune tolerance induction, and the efficacy of a non-depleting anti-CD4 monoclonal antibody should be investigated in humans. The majority of MPS I individuals in the UK have… Advisors/Committee Members: JONES, SIMON S, Bigger, Brian, Jones, Simon.

Subjects/Keywords: Mucopolysaccharidosis Type I; Mucopolysaccharidosis Type III; Hurler syndrome; Hurler-Scheie syndrome; Scheie syndrome; Sanfilippo disease; Newborn screening; Genotype-phenotype correlations; Immune tolerance induction; Antibodies; Anti-drug antibodies; Enzyme replacement therapy; Bone marrow transplantation; Haematopoietic stem cell transplantation; Substrate reduction therapy; Clinical trials; Clinical trial design; Genistein; Genistein aglycone; Glycosaminoglycans; Heparan sulfate

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

APA (6^th Edition):

Ghosh, A. (2018). Improving Diagnosis and Treatment Outcomes in Mucopolysaccharidoses. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317761

Chicago Manual of Style (16^th Edition):

Ghosh, Arunabha. “Improving Diagnosis and Treatment Outcomes in Mucopolysaccharidoses.” 2018. Doctoral Dissertation, University of Manchester. Accessed January 18, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317761.

MLA Handbook (7^th Edition):

Ghosh, Arunabha. “Improving Diagnosis and Treatment Outcomes in Mucopolysaccharidoses.” 2018. Web. 18 Jan 2021.

Vancouver:

Ghosh A. Improving Diagnosis and Treatment Outcomes in Mucopolysaccharidoses. [Internet] [Doctoral dissertation]. University of Manchester; 2018. [cited 2021 Jan 18]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317761.

Council of Science Editors:

Ghosh A. Improving Diagnosis and Treatment Outcomes in Mucopolysaccharidoses. [Doctoral Dissertation]. University of Manchester; 2018. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317761

University of Manchester

14. Ghosh, Arunabha. Improving diagnosis and treatment outcomes in mucopolysaccharidoses.

Degree: PhD, 2019, University of Manchester

URL: https://www.research.manchester.ac.uk/portal/en/theses/improving-diagnosis-and-treatment-outcomes-in-mucopolysaccharidoses(dc0c170c-e8ce-4004-ba0d-9df214b393d1).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.799376

► Mucopolysaccharidoses (MPS) are a heterogenous group of disorders caused by inherited deficiencies of enzymes involved in glycosaminoglycan degradation. Two such disorders, MPS I and MPS… (more)

▼ Mucopolysaccharidoses (MPS) are a heterogenous group of disorders caused by inherited deficiencies of enzymes involved in glycosaminoglycan degradation. Two such disorders, MPS I and MPS III, present distinct treatment challenges. In MPS I, significant areas of unmet need remain despite the existence of two therapies: enzyme replacement therapy (ERT) and haematopoietic stem cell transplantation (HSCT), the latter being the treatment choice in severe MPS I (Hurler syndrome). Several strategies to optimise diagnosis and treatment are considered: (1) the safety and utility of combined ERT and HSCT, a frequently used, though not universal, treatment approach; (2) mitigation of the antibody response to ERT, which may negatively impact treatment efficacy; (3) the development of genotype-phenotype relationships that would be relevant for the implementation of newborn screening, and could enable earlier initiation of therapy and improve outcomes. MPS III is a predominantly neurological disease with no existing treatment. The efficacy of genistein aglycone, a potential substrate reduction therapy, was investigated in MPS III patients. In a retrospective review of 81 MPS I patients who received peri-transplant ERT, overall survival was 88% and engrafted survival was 81% (median follow-up 46 months). Improvement in cardiopulmonary disease status during ERT enabled selected individuals to tolerate full intensity conditioning. An open-label study of prophylactic immune tolerance induction using methotrexate in three MPS I Hurler individuals found that one or three weeks of oral methotrexate did not prevent high titre anti-drug antibody responses. However, in an MPS I mouse model, two courses of an anti-CD4 monoclonal antibody prevented antibody responses to ERT in seven out of eight mice (87.5%). Analysis of genotypes and phenotypic severity in a cohort of 286 MPS I patients identified 63 IDUA variants, of which 20 were novel, and associations with phenotypic severity were assigned for all but six. A total of 37 variants were only identified in a single individual or family, but this accounted for only 13% of individuals. In 57% of individuals, both alleles were one of nine common variants. A double-blinded, randomised, placebo-controlled clinical trial of high dose genistein aglycone (160mg/kg/day) in MPS III found that 12 months of genistein did not result in a significantly lower concentration of cerebrospinal fluid heparan sulfate than placebo (p=0.26), and the size of reduction (5.5%) was not clinically meaningful. No deviation from natural history in neuropsychological measures was observed. These findings suggest potential approaches to improving diagnosis and treatment. Combined ERT and HSCT in MPS I has clinical utility for selected high risk individuals, though patients are known to develop anti-drug antibodies. These could be mitigated by immune tolerance induction, and the efficacy of a non-depleting anti-CD4 monoclonal antibody should be investigated in humans. The majority of MPS I individuals in the UK have…

Subjects/Keywords: Bone marrow transplantation; Haematopoietic stem cell transplantation; Substrate reduction therapy; Clinical trials; Genistein; Genistein aglycone; Glycosaminoglycans; Heparan sulfate; Clinical trial design; Enzyme replacement therapy; Immune tolerance induction; Antibodies; Mucopolysaccharidosis Type I; Mucopolysaccharidosis Type III; Hurler syndrome; Anti-drug antibodies; Hurler-Scheie syndrome; Sanfilippo disease; Newborn screening; Genotype-phenotype correlations; Scheie syndrome

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

APA (6^th Edition):

Ghosh, A. (2019). Improving diagnosis and treatment outcomes in mucopolysaccharidoses. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/improving-diagnosis-and-treatment-outcomes-in-mucopolysaccharidoses(dc0c170c-e8ce-4004-ba0d-9df214b393d1).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.799376

Chicago Manual of Style (16^th Edition):

Ghosh, Arunabha. “Improving diagnosis and treatment outcomes in mucopolysaccharidoses.” 2019. Doctoral Dissertation, University of Manchester. Accessed January 18, 2021. https://www.research.manchester.ac.uk/portal/en/theses/improving-diagnosis-and-treatment-outcomes-in-mucopolysaccharidoses(dc0c170c-e8ce-4004-ba0d-9df214b393d1).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.799376.

MLA Handbook (7^th Edition):

Ghosh, Arunabha. “Improving diagnosis and treatment outcomes in mucopolysaccharidoses.” 2019. Web. 18 Jan 2021.

Vancouver:

Ghosh A. Improving diagnosis and treatment outcomes in mucopolysaccharidoses. [Internet] [Doctoral dissertation]. University of Manchester; 2019. [cited 2021 Jan 18]. Available from: https://www.research.manchester.ac.uk/portal/en/theses/improving-diagnosis-and-treatment-outcomes-in-mucopolysaccharidoses(dc0c170c-e8ce-4004-ba0d-9df214b393d1).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.799376.

Council of Science Editors:

Ghosh A. Improving diagnosis and treatment outcomes in mucopolysaccharidoses. [Doctoral Dissertation]. University of Manchester; 2019. Available from: https://www.research.manchester.ac.uk/portal/en/theses/improving-diagnosis-and-treatment-outcomes-in-mucopolysaccharidoses(dc0c170c-e8ce-4004-ba0d-9df214b393d1).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.799376

University of Cincinnati

15. Sane, Rucha S. Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2006, University of Cincinnati

URL: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615

► Tamoxifen is a widely used antiestrogen in the treatment and prevention of breast cancer. Some of its unresolved problems include the occurrence of drug-drug interactions,… (more)

▼ Tamoxifen is a widely used antiestrogen in the treatment and prevention of breast cancer. Some of its unresolved problems include the occurrence of drug-drug interactions, acquired resistance and endometrial carcinogenesis. Here we hypothesized that tamoxifen and/or its metabolites induce drug metabolizing enzymes and transporters and these inductive effects entail activation of the human pregnane X receptor (hPXR). First, we evaluated the activity and expression of key phase I and II enzymes, Cytochrome P450 (CYP) 3A4 and UDP-Glucuronyltransferase and drug transporter, P-glycoprotein, in primary human hepatocytes and LS174T colon carcinoma cell line. Tamoxifen and 4-hydroxytamoxifen (4-OHT) exhibited significant induction of CYP3A4 and moderate induction of UGT1A1 and P-gp in hepatocytes. In LS174T cells tamoxifen/4OHT moderately induced UGT1A1 and P-gp but failed to induce CYP3A4. This apparent tissue-specific difference in CYP3A4 induction by tamoxifen may be related to the observed differences in the expression of transcription factors such as hPXR and glucocorticoid receptor in (GRá) these cells. Next, in promoter-reporter assays we observed that tamoxifen/4-OHT are efficient activators of hPXR. Attenuation of hPXR in human hepatocytes employing siRNA against hPXR caused a corresponding decrease in the extent of CYP3A4 induction indicating that induction by tamoxifen/4-OHT primarily results from their interactions with hPXR. Examination of the role of other receptors revealed that GRá potentiates hPXR mediated CYP3A4 promoter activation by the antiestrogens. However, activated estrogen receptor appeared to suppress the basal transcription of CYP3A4 in these assays. Based on our pre-clinical data, we initiated a clinical study to assess CYP3A4 induction in breast cancer patients who are prescribed the tamoxifen regimen (20 mg/day). Midazolam, a drug metabolized by CYP3A4, was employed as a probe for CYP3A4 activity. In four patients evaluated thus far, we have noted a distinct trend towards increased midazolam clearance, indicative of increased CYP3A4 activity, following steady state tamoxifen dosing (day 42) compared to basal CYP3A4 activity, evaluated prior to initiating tamoxifen therapy. Thus, our study suggests that tamoxifen/4-OHT upregulate CYP3A4, which has implications for optimizing the clinical use of tamoxifen and the development of new antiestrogens that do not carry the risk of drug interactions, acquired drug resistance and endometrial carcinogenesis. Advisors/Committee Members: Desai, Rucha (Advisor).

Subjects/Keywords: Health Sciences, General; Tamoxifen; CYP3A4; Cytochrome P450; Enzyme induction; drug metabolism; human hepatocytes; UDP-glucuronosyl transferase; P-glycoprotein; Pregnane X Receptor; PXR; LS174T

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

APA (6^th Edition):

Sane, R. S. (2006). Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615

Chicago Manual of Style (16^th Edition):

Sane, Rucha S. “Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications.” 2006. Doctoral Dissertation, University of Cincinnati. Accessed January 18, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615.

MLA Handbook (7^th Edition):

Sane, Rucha S. “Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications.” 2006. Web. 18 Jan 2021.

Vancouver:

Sane RS. Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications. [Internet] [Doctoral dissertation]. University of Cincinnati; 2006. [cited 2021 Jan 18]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615.

Council of Science Editors:

Sane RS. Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications. [Doctoral Dissertation]. University of Cincinnati; 2006. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615

University of Florida

16. Kopnisky, Kathy L., 1964-. Modulation of lipopolysaccharide and cytokine stimulated inducible nitric oxide synthase by angiotensin II.

Degree: 1996, University of Florida

URL: https://ufdc.ufl.edu/AA00052901

Subjects/Keywords: Astrocytes; Brain; Cytokines; Endotoxins; Messenger RNA; Microglia; Nitrites; Oxides; Rats; Receptors; Angiotensin II – pharmacology ( mesh ); Astrocytes ( mesh ); Cytokines ( mesh ); Department of Physiology thesis Ph.D ( mesh ); Endotoxins ( mesh ); Enzyme Induction ( mesh ); Enzyme Induction – drug effects ( mesh ); Interferon Type II ( mesh ); Interleukin-1 ( mesh ); Lipopolysaccharides ( mesh ); Nitric-Oxide Synthase – drug effects ( mesh ); Protein Kinase C – pharmacology ( mesh ); Rats ( mesh ); Research ( mesh ); Tumor Necrosis Factor ( mesh )

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

APA (6^th Edition):

Kopnisky, Kathy L., 1. (1996). Modulation of lipopolysaccharide and cytokine stimulated inducible nitric oxide synthase by angiotensin II. (Thesis). University of Florida. Retrieved from https://ufdc.ufl.edu/AA00052901

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):

Kopnisky, Kathy L., 1964-. “Modulation of lipopolysaccharide and cytokine stimulated inducible nitric oxide synthase by angiotensin II.” 1996. Thesis, University of Florida. Accessed January 18, 2021. https://ufdc.ufl.edu/AA00052901.

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

MLA Handbook (7^th Edition):

Kopnisky, Kathy L., 1964-. “Modulation of lipopolysaccharide and cytokine stimulated inducible nitric oxide synthase by angiotensin II.” 1996. Web. 18 Jan 2021.

Vancouver:

Kopnisky, Kathy L. 1. Modulation of lipopolysaccharide and cytokine stimulated inducible nitric oxide synthase by angiotensin II. [Internet] [Thesis]. University of Florida; 1996. [cited 2021 Jan 18]. Available from: https://ufdc.ufl.edu/AA00052901.

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

Council of Science Editors:

Kopnisky, Kathy L. 1. Modulation of lipopolysaccharide and cytokine stimulated inducible nitric oxide synthase by angiotensin II. [Thesis]. University of Florida; 1996. Available from: https://ufdc.ufl.edu/AA00052901

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

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Open Access Theses and Dissertations