Dissertations / Theses on the topic 'Drug therapy'
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O'Callaghan, Christopher. "Aerosolised drug therapy in infancy." Thesis, University of Nottingham, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305089.
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Pandie, Mishal. "Drug-drug interactions between antiretrovirals and bedaquiline." Master's thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/27401.
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Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide. People living with HIV are particularly susceptible to TB infection, and treatment of HIV-TB co-infection is challenging for multiple reasons, including potential drug-interactions. Drug-resistant TB is difficult to treat and is associated with high treatment failure rates, mainly because the antimycobacterial drugs currently available are ineffective against drug-resistant TB. Bedaquiline is a new antimycobacterial drug which has shown great promise through its excellent efficacy for treating drug-resistant TB. Being a new drug, however, potential drug interactions with antiretrovirals are a major concern. Bedaquiline is metabolized in the liver by an enzyme called cytochrome P450 3A (CYP3A). The antiretrovirals nevirapine, efavirenz, and lopinavir/ritonavir (LPV/r) can affect the activity of this enzyme, and consequently affect the concentration of bedaquiline in the patient's blood. Nevirapine and efavirenz increase the activity of CYP3A, which may result in increased metabolism of bedaquiline, thus decreasing the concentration of bedaquiline, with consequent risk of treatment failure or the further development of drug-resistance. LPV/r inhibits the CYP3A enzyme, which may result in decreased bedaquiline metabolism, thus causing high concentration of bedaquiline in the blood, with consequent risk of toxicity. We conducted a pharmacokinetic study in 43 adult patients with drug-resistant TB to evaluate the drug-interactions between bedaquiline and the antiretrovirals nevirapine and LPV/r. We did serial measurements of the bedaquiline concentration in their plasma over 48 hours, and compared these concentrations in patients who were on antiretroviral and those who were not on antiretrovirals. Our results showed that nevirapine had no significant effect on bedaquiline concentrations, while patients on LPV/r had bedaquiline concentrations 2 fold higher than patients not on antiretrovirals. We could not determine the clinical significance of this, but recommend that patients receiving LPV/r and bedaquiline in combination must be closely monitored for side-effects.
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Mathis, Leigh Ann. "Student Psychotropic Drug Use, Past Therapy Experience and Length of Therapy." TopSCHOLAR®, 2008. http://digitalcommons.wku.edu/theses/49.
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Alfahad, Mohanad Abdul-Satar Mahmood. "Pro-drug strategies for pancreatic cancer therapy." Thesis, Keele University, 2018. http://eprints.keele.ac.uk/4534/.
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Pancreatic cancer is the fourth main cancer in the western world. Currently the only chemotherapy available clinically is gemcitabine. However, gemcitabine treatment only proves effective in 23.8% of patients. Nano-structures (< 120 nm) are capable of entering the highly permeable blood capillaries which supply the rapidly growing tumours. Once inside the capillaries they accumulate and are retained in the tumour as a result of the poor lymphatic drainage. This allows for a deeper tissue penetration which is otherwise difficult to achieve. Hybrid nanoparticles with an iron oxide core covered by gold shell (HNPs) have shown great potential for anti-cancer therapies. The magnetic iron oxide cores and the surface plasmon resonance (SPR) properties of the gold surface provide the HNPs with the capabilities of diagnostic imaging and drug delivery, making them true theranostic agents. A novel prodrug of gemcitabine has been developed by a regioselective coupling of gemcitabine and lipoic acid, itself a potent antioxidant. Gemcitabine-N-lipoate (GL) was obtained in a one-pot synthesis and the optimum conditions for the reaction were established. GL prodrug loading on to the HNPs surface was confirmed and the release profile of gemcitabine from the GL-HNPs formulation was studied at pH 3.6, 5.6 and 7.4 utilising different temperature conditions (20, 37, 44 °C) using RPMI serum free media under sink conditions. The data showed the stability of the formulation at pH 7.4, 20 °C while the optimum release conditions for gemcitabine from the GL-HNPs formulation were at pH 5.6, 44 °C with the highest release of 41.1% recorded after 24 hrs. III Preliminary in vitro MTT assay together with the drug uptake study show the superior inhibitory effect of the GL-HNPs formulation on the cell viability over gemcitabine after 24 hrs which indicates faster uptake of the formulation, however the overall effect of gemcitabine is greater after 48 hrs which is mainly due to the slow release of gemcitabine from the formulation. The behaviour of the GL-HNPs formulation as a drug delivery system shows a great potential for the system to act as a theranostic tool and to overcome the significant drawbacks associated with gemcitabine.
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Morrow, D. I. J. "Novel Drug Delivery Approaches to Photodynamic Therapy." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502072.
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Yung, Bryant Chinung. "NANOPARTICLE DRUG DELIVERY SYSTEMS FOR CANCER THERAPY." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417614665.
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Zi, Hong. "Polymers for drug delivery in cancer therapy /." May be available electronically:, 2008. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Murphy, Jennifer. "Therapy and Punishment: Negotiating Authority in the Management of Drug Addiction." Diss., Temple University Libraries, 2008. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/8969.
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SociologyPh.D.
Throughout the twentieth century, many behaviors previously considered criminal or immoral were instead defined as medical problems. This process is often referred to as the medicalization of deviance. Like many other behaviors once considered deviant, drug and alcohol abuse has been medicalizing, in a process that accelerated during the latter half of the twentieth century. Despite this movement along the path toward medicalization, drug use, and alcohol use to a lesser extent, are still also sanctioned and managed by the criminal justice system, resulting in a medical-legal-moral hybrid definition of these issues. Today we find instances where these two institutions overlap significantly. At the same time, their mutual involvement in defining and managing drug use is inconsistent. This research uses a qualitative research design to study how this medical-legal-moral hybrid definition of drug use and addiction is discussed and negotiated by various institutions that label and manage individuals who use drugs. I examined this issue by conducting interviews and observations in Philadelphia's Drug Treatment Court as well as in two outpatient drug treatment programs. Results indicate that individuals in both settings frame addiction as a "disease," although the definition is ambiguous and inconsistent. The court and the treatment programs use similar language and methods for assessing substance abuse and how to deal with it. Both also extend the definition of "addiction" to include aspects not directly related to the consumption of drugs or alcohol but to the "drug lifestyle" that includes selling drugs. Still, in neither location is a comprehensive, clear definition of "addiction" promoted and used consistently. This ambiguity results in an overlap of therapeutic and punitive methods to handle the individual's drug usage. In addition, both settings benefit from their interaction and cooperation in managing individuals with substance abuse problems, indicating that rather than moving toward a purely "medical" way of dealing with substance abuse, or placing the issue more firmly in the realm of the criminal justice system, the current mix of moral, criminal and medical methods of labeling and managing substance abuse problems may be more stagnant than the medicalization of deviance thesis suggests.
Temple University--Theses
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Deshauer, Dorian. "Enrichment-discontinuation designs in psychiatric drug maintenance therapy." Thesis, University of Ottawa (Canada), 2007. http://hdl.handle.net/10393/27829.
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Objective. This thesis tests the validity of a randomized controlled trial variant, the enrichment-discontinuation design (also called a randomized discontinuation design) against gold-standard classic RCT's using published trials of psychiatric drug therapy. Methods. A series of systematic reviews were conducted to identify all maintenance trials of mood stabilizers and antidepressants. Planned comparisons between enrichment discontinuation trials and gold standard classic RCT's were conducted. Finally, a sample of research literature was reviewed to identify the extent to which the limits of enrichment discontinuation trials were identified. Results. There was a non-statistically significant trend favoring drugs used in open phases vs classic RCT's. The lack of extended classic RCT's of psychiatric drugs is poorly recognized. Conclusion. Enrichment discontinuation designs dominated the evidence base supporting psychiatric drug maintenance. Bias cannot be ruled out. Limits to the design are poorly recognized in the literature. For further details, refer to the executive summary.
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Massicotte, Eric M. "Adjunctive drug therapy for treatment of experimental hydrocephalus." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0011/MQ53184.pdf.
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Grosset, Katherine Anne. "Therapy concordance and drug adherence in Parkinson's disease." Thesis, University of Glasgow, 2005. http://theses.gla.ac.uk/2341/.
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Chapter 1 gives an overview of the relevance of studying therapy adherence in Parkinson’s disease. Chapter 2 examines drug induced neurological syndromes and considers the validity of patients’ concerns about taking prescribed medications. Chapter 3 compares different methods of assessing therapy adherence. Chapter 4 studies factors associated with sub-optimal medicine usage in 54 patients. Chapter 5 reports a study of patient perceived involvement with management decisions and an assessment of satisfaction with the movement disorder service in 107 patients. Chapter 6 explores patients’ beliefs about antiparkinson medication in 129 patients. Chapter 7 examines the effect on Parkinson’s patients of emerging data about drug side effects, specifically fibrosis due to ergot-based dopamine agonists. Chapter 8 reports on an educational intervention designed to improve Parkinson drug timing compliance. In summary, this thesis provides important new information about medicine taking in Parkinson’s disease. A fifth of PD patients take less than 80% of prescribed antiparkinson medication. Electronic monitoring is the only reliable method of accurately detecting sub-optimal medication usage. Patients who take less than 80% of prescribed medicines are more likely to be younger, have concomitant depression, be prescribed more tablets per day and have poorer quality of life. Patients are more satisfied if they are involved in management decisions and have increased intention to comply with prescribed medication if there is better communication. Poorer quality of life is associated with less intention to comply with prescribed medication. Timing of medication intake is generally irregular but can be improved by informing patients of the continuous dopaminergic theory and providing specific drug timings. Once daily drugs are taken more consistently than drugs with more frequent doses.
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Antona, Annamaria. "Repurposing of psychotropic drugs for cancer therapy." Doctoral thesis, Università del Piemonte Orientale, 2021. http://hdl.handle.net/11579/127826.
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Despite improvements in cancer therapy, overall survival for most cancer types has changed a little in the past decades. Drug repositioning represents a promising approach for discovering new therapeutic strategies for cancer therapy.
Since several epidemiological studies reported lower cancer incidence in individuals receiving long term psychotropic drugs treatment, in this project we investigated 27 psychotropic drugs for their cytotoxic activity in several cancer cell lines. Consistent with the cationic amphiphilic structure of the most cytotoxic compounds, we investigated their effect on mitochondrial and lysosomal compartments. Penfluridol, ebastine, pimozide, fluoxetine, fluspirilene and nefazodone showed significant cytotoxicity, in the low micromolar range, in all cell lines tested.
In MCF7 cells these drugs triggered mitochondrial membrane depolarization, increased the acidic vesicular compartments and induced phospholipidosis. Neither caspase nor autophagy inhibitors rescued cells from death induced by fluoxetine, fluspirilene and nefazodone. Treatment with 3-methyladenine rescued cell death induced by pimozide and spiperone. Conversely, inhibition of lysosomal cathepsins significantly reduced cell death induced by ebastin, penfluridol, pimozide, spiperone and mildly by fluoxetine. Lastly, spiperone caused apoptosis in colorectal and breast. Our unpublished data on the characterization of spiperone activity on adherent and stem-like colorectal cancer cells demonstrated that its cytotoxicity is linked to perturbations of intracellular calcium (Ca2+) homeostasis, which likely result in mitochondrial Ca2+ overload and membrane depolarization, cell cycle block in G1 phase, and apoptosis. Spiperone induced a PLC dependent Ca2+ release from the endoplasmic reticulum (ER) along with ER stress and unfolded protein response activation, resulting in CHOP upregulation.
Altogether these data support the clinical development of psychotropic drugs for cancer therapy.
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Gustafsson, Maria. "Optimizing drug therapy among people with dementia : the role of clinical pharmacists." Doctoral thesis, Umeå universitet, Geriatrik, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-118309.
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Background: Drugs are one of the cornerstones in the management of many diseases. In general, drugs are used for diagnosis, prevention, mitigation of symptoms, and, sometimes, to cure disease. However, drug treatment in elderly people, especially those with dementia and cognitive impairments, may involve significant risk of adverse drug events. The aim of this thesis was to identify the extent of potentially inappropriate drug treatment among people with dementia and cognitive impairment and to assess the occurrence and character of drug-related problems that lead to acute hospital admissions. Another aim was to assess the potential impact of a comprehensive medication review conducted by clinical pharmacists as part of a health care team on quality of patients’ drug therapy and drug-related hospital readmission rates. Method: Long-term use of antipsychotic/psychotropic drugs and associated factors were investigated among 344 and 278 people respectively with dementia living in specialized care units. Trends in the prescribing of potentially inappropriate drugs between 2007 and 2013, comprising 2772 and 1902 people, living in nursing homes in the county of Västerbotten, were assessed using six national quality indicators. Data on drug use, function in the activities of daily living, cognitive function and behavioral and psychological symptoms were collected using the Multi-Dimensional Dementia Assessment Scale. Further, an investigation of a separate corresponding population from 2012 was done, where potentially inappropriate drug use was measured before and after a total of 895 medication reviews. Finally, a randomized, controlled trial was carried out among people 65 years or older with dementia or cognitive impairment in internal medicine and orthopedic wards at two hospitals in northern Sweden. The proportion of hospital admissions that were drug-related were estimated, and also whether comprehensive medication reviews conducted by clinical pharmacists as part of a health care team could affect the risk of drug-related hospital readmissions. Results: Antipsychotic and other psychotropic drugs were frequently prescribed to people with dementia living in specialized care units for prolonged periods. Associations were found between behavioral and psychological symptoms and different psychotropic drugs. The extent of potentially inappropriate drug use declined between 2007 and 2013. In the separate corresponding population from 2012, the frequency of potentially inappropriate drug use was significantly reduced among people who underwent medication reviews. Hospitalizations due to drug-related problems among old people with dementia or cognitive impairment were prevalent. We found that inclusion of a clinical pharmacist in the health care team significantly reduced the risk of drug-related 30-day and 180-day readmissions. However, in a subset of patients with concomitant heart failure no effect was seen. Conclusion: Among patients with dementia or cognitive impairment long-term treatment with antipsychotic and other psychotropic drugs is common. The results indicate that these drugs are prescribed to treat behavioral and psychological symptoms among cognitively impaired individuals, despite limited evidence of their efficacy and the high risk of adverse effects. Drug-related problems, such as adverse drug reactions, constituted a major cause of hospital admissions. By reducing potentially inappropriate drug use and optimizing overall drug therapy, inclusion of clinical pharmacists in a health care team might improve the quality of patient care and reduce the risk of hospital readmissions among people with dementia.
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Rodríguez, Amigo Beatriz. "Light-sensitive nanocarriers for drug delivery in photodynamic therapy." Doctoral thesis, Universitat Ramon Llull, 2018. http://hdl.handle.net/10803/462210.
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Aquesta tesi aprofundeix en l’estudi de nanotransportadors com a sistemes de vehiculització i en alguns casos, alliberació de fotosensibilitzadors emprats en teràpia fotodinàmica. S’han fet servir dos nanotransportadors de naturalesa diferent: proteïnes i liposomes.
En primer lloc s’ha investigat els complexos formats entre la hipericina i les proteïnes apomioglobina i β-lactoglobulina. S’han estudiat les característiques fisicoquímiques i fotofísiques, avaluant l’activitat antimicrobiana en front a bacteris gram-positius i gram-negatius. En ambdues matrius proteiques el fotosensibilitzador es troba majoritàriament en forma monomèrica, preservant les seves propietats fotofísiques i formant un complex estable. En el cas de la β-lactoglobulina s’estudia a més, la formació del complex amb l’adició d’un 20% de DMSO com a co-solvent, fet que millora les propietats fotofísiques en detriment de la capacitat antimicrobiana. Ambdós complexos proteics son efectius contra bacteris gram-positius però no contra gram-negatius. Per altra banda, es demostra que la hipericina incorporada a la cavitat de l’apomioglobina pot ser utilitzada en microscòpia de super-resolució STED. Amb aquesta tècnica es pot monitoritzar els llocs d’unió del fotosensibilitzador a la membrana dels bacteris. Així mateix, s’estudia l’ús de la β-lactoglobulina com a portador dual d’hipericina i àcid retinoic. En aquest últim sistema multi-component s’avaluen les propietats fotofísiques per a verificar la formació i estabilitat del complex.
En segon lloc, es desenvolupa un nanovehicle per la seva aplicació en teràpia combinada en el qual s’incorporen fàrmacs quimioterapèutics convencionals amb agents fotosensibilitzants, per superar resistències i millorar l’eficàcia dels tractaments individuals. Amb aquest objectiu, s’han dissenyat i estudiat dues formulacions liposomals diferents, ambdues amb el mateix fotosensibilitzador però encapsulant diferents agents quimioterapèutics. Es preparen formulacions bimodals on s’incorporen els dos agents al mateix vehicle i els seus homòlegs unimodals, amb la incorporació única d’un dels dos agents. S’han avaluat les característiques fisicoquímiques, fotofísiques i fotobiològiques de les suspensions bimodals i unimodals. La lozalització subcel·lular demostra que cada principi actiu es localitza a orgànuls diferents desencadenant rutes de senyalització cel·lular diferents, eludint els possibles mecanismes de resistència. El tractament in vitro en cèl·lules cancerígenes amb aquests sistemes tenen un efecte prometedor, ja que com a mínim presenten un comportament additiu respecte els tractaments individuals. Finalment, s’ha avaluat el potencial de la vehiculització activa mitjançant la unió covalent d’un anticòs monoclonal a la superfície, el que millora lleugerament els resultats per una de les dues formulacions.Esta tesis profundiza en el estudio de nanotransportadores como sistema de vehiculización y en algunos casos, liberación de fotosensibilizadores empleados en terapia fotodinámica. Se emplean dos nanotransportadores de naturaleza distinta: proteínas y liposomas. En primer lugar se han investigado los complejos formados entre hipericina y las proteínas apomioglobina y β-lactoglobulina. Se han estudiado las características fisicoquímicas y fotofísicas, evaluando la actividad antimicrobiana frente bacterias gram-positivas y gram-negativas. En ambas matrices proteicas el fotosensibilizador se encuentra mayoritariamente en forma monomérica, preservando sus propiedades fotofísicas y formando un complejo estable. En el caso de la β-lactoglobulina se estudia además, la formación del complejo con la adición del 20% de DMSO como co-solvente, lo que mejora las propiedades físicas pero sorprendentemente, empeora la capacidad antimicrobiana. Ambos complejos proteicos son efectivos contra bacterias gram-positivas, pero no contra gram-negativas. Además, se demuestra que la hipericina en la cavidad de la apomioglobina es capaz de realizar microscopía de super-resolución STED, mediante la cual se puede monitorizar los sitios de unión a las bacterias. Asimismo, se ha estudiado la β-lactoglobulina como portador dual de hipericina y ácido retinoico. En este último sistema multi-componente se evalúan las propiedades fotofísicas para verificar la formación y estabilidad del complejo. En segundo lugar, se desarrolla un nanovehículo para su uso en terapia combinada en el que se incorpora fármacos quimioterapéuticos convencionales con agentes fotosensibilizantes, para superar las resistencias y mejorar la eficacia de los tratamientos individuales. Con este objetivo, se han diseñado y estudiado dos formulaciones liposomales diferentes, ambas con el mismo fotosensibilizador, pero con diferentes agentes quimioterapéuticos. Se preparan las formulaciones bimodales con ambos agentes en el mismo vehículo además de sus homólogos unimodales, con la incorporación única de uno de los dos agentes. Se han evaluado las características fisicoquímicas, fotofísicas y fotobiológicas de las suspensiones bimodales y unimodales. La localización subcelular demuestra que cada principio activo se localiza en orgánulos diferentes desencadenando rutas de señalización celular diferentes, eludiendo los posibles mecanismos de resistencia. El tratamiento in vitro en células cancerígenas de estos sistemas tiene un efecto prometedor siendo al menos aditivo en comparación con los tratamientos individuales. Finalmente, se ha evaluado el potencial de la vehiculización activa mediante la unión covalente de un anticuerpo monoclonal en la superficie, lo que lleva a resultados ligeramente superiores para una de las dos formulaciones.
This thesis reports the study of nanocarriers as drug delivery systems for photosensitisers in photodynamic therapy. Proteins and liposomes are the two nanovehicles of different nature used for this purpose. Beginning with the proteins, the complexes formed between hypericin and the proteins apomyoglobin and β-lactoglobulin have been explored. The physicochemical and photophysical properties have been studied, as also assessing their photoantibacterial activity against Gram-positive and Gram-negative bacteria. In both protein scaffolds the photosensitiser is found mainly in monomeric form, preserving its fluorescence and singlet oxygen photosensitising properties and yielding a stable complex. In the case of β-lactoglobulin, the complex formation has also been tested with the addition of a 20% DMSO as a co-solvent, which improves the photophysical properties but surprisingly, worsens its antimicrobial activity. Both protein complexes are effective against Gram-positive but not against Gram-negative bacteria. Moreover, it has been proved that hypericin, inside the apomyoglobin cavity, can perform STED microscopy through which its localization in bacteria can be monitored. Additionally, the suitability of β-lactoglobulin as a dual carrier for hypericin and acid retinoic has also been exploited. In this last multi-component system, the photophysical properties have been evaluated to confirm the formation and complex stability. Secondly, a nanocarrier for its use in combined therapy has been developed, in which conventional chemotherapeutic drugs are combined with photosensitising agents to overcome resistance and improve the effectiveness of the individual treatments. For this purpose, two different liposome formulations have been designed and studied with a common photosensitiser but different anti tumour drugs. The bimodal formulations with both agents entrapped and their unimodal counterparts, having each drug loaded in separate liposomes, have been evaluated. The physicochemical, photophysical and photobiological properties of bimodal and unimodal suspensions have been studied. The subcellular localization shows different organelle accumulation by each agent, triggering different key signals transduction pathways, eluding the cellular resistance mechanisms. The treatment in vitro of these multi-component liposomes with cancer cells has a promising effect, since at least an additive outcome is observed when compared with the individual treatments. Finally, we have explored the potential of active targeting strategies by covalently linking a monoclonal antibody to the surface, leading to slightly greater outcomes for one of the liposomal formulations.
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Gilissen, Leonardus (Lennard) Petrus Lucia. "Therapeutic drug monitoring of thiopurine therapy in IBD patients." [Maastricht : Maastricht : Maastricht University] ; University Library, Universiteit Maastricht [host], 2008. http://arno.unimaas.nl/show.cgi?fid=11069.
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Arif, Khalid. "Evaluation of hormonal receptors in breast cancer drug therapy." Thesis, University of Lincoln, 2014. http://eprints.lincoln.ac.uk/14682/.
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Breast cancer is the most common type of cancer in women worldwide. Approximately two-thirds of breast cancers are oestrogen receptor positive (ER+), which are activated via oestrogen dependent and independent mechanisms. The pathogenic role of oestrogen in breast cancer is well established, thus, targeting ER becomes an essential target in breast cancer anti-hormonal therapy. Tamoxifen is the most important anti-hormonal therapeutic agent which has been used as the gold standard in the treatment of ER+ breast cancer patients. Tamoxifen acts by competing with oestrogen for binding to the ER and reduces the transcription of oestrogen dependent genes. However, approximately 30-50% of patients either fail to respond or eventually become resistant to tamoxifen via not fully elucidated mechanisms, resulting in a serious clinical challenge in breast cancer management. Also there is increasing evidence that cancers are driven by cancer stem cells which are characterised by their ability for self renewal and resistance to drug therapies. Therefore the aim of this study was to evaluate the role of oestrogen receptors in both de novo and acquired tamoxifen resistant breast cancer. Study the influence of stem cell factors and the embryonic stemness gene in both MDA-MB-231 and MCF7/Tmx breast cancer cell lines with respect to the hypothesis that anti-stem cell factor and silencing of the Nanog may restore sensitivity to tamoxifen and enhance cell apoptosis. Qualitative and quantitative assays showed significant expression of CD44, PgP, MRP1 and embryonic markers (Nanog, Oct3/4 and Sox2) in MDA-MB-231 and MCF7/Tmx cells. Independently, MDA-MB-231, MCF7/Tmx and parental MCF7/WT cells were treated with monoclonal anti-stem cell factor (ACSF) and interfered with Nanog short interference RNA (siRNA), then growth rate, drug accumulation and apoptosis were assessed in response to 4-hydroxtamoxifen (4-OHT). Quantitative analysis of the influx and efflux rate was performed using the Technetium (99mTc) sestamibi assay in response to blocking SCF. iv Results show a significant apoptosis enhancement after treatment with ASCF in both MDA-MB-231 and MCF/Tmx cells (P<0.005) and a significant increase in the influx rate of 99mTc-MIBI in MDA-MB-231 cells. Growth rate and apoptosis markers were assessed prior to and after the silencing of Nanog gene. Results show a significant increase in apoptosis and reduction in the growth rate in both MDA-MB-231 and MCF/Tmx cells (P<0.005). This study demonstrates that multi drug resistance is mainly a phenomenon of acquired tamoxifen resistance, but not de novo resistance. The inhibition of SCF could inhibit cell proliferation and significantly increases cell sensitivity to tamoxifen in MDA-MB-231 and acquired tamoxifen resistant cells MCF7/Tmx. This study identified a high expression of embryonic markers Nanog, Oct3/4 and Sox2 in both MDA-MB-231 and MCF7/Tmx cells and that the silencing of the Nanog gene reduces cell proliferation and increases apoptosis in MDA-MB-231 and MCF7/Tmx cells. In conclusion, the results suggest that the neutralisation of stem cell factor may play an important role in enhancing tamoxifen response in ER- cells and less in acquired tamoxifen resistant breast cancer cells, via enhancing drug accumulation. The positive association of the embryonic markers with negative (ER-) and acquired tamoxifen resistant breast cancer cells could be used as prognostic markers and the knockdown of these transcription markers could enhance the response to tamoxifen and could be used in the management of breast cancer.
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Lui, Yuan Siang. "Developing sustained dual-drug therapy for tendon sports injuries." Thesis, Loughborough University, 2016. https://dspace.lboro.ac.uk/2134/23739.
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Tendon plays an important role in regulating body locomotion and providing additional stability to the body. However, tendon is susceptible to injuries and the healing process could be devastating along with the several issues, namely adhesion formations, slow healing and failure at fixation sites, which have deferred the success of proper tendon healing via tendon tissue engineering. This dissertation thus aims to create a sustained dual-drug therapy to address these issues. For adhesion formation, naproxen sodium (NPS) has been shown to be able to avoid this symptom through inhibiting inflammation process.
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Liu, Yang. "Development of Novel Drug Delivery Systems for Cancer Therapy." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu153105342400785.
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Dore, David D. "Benefits and consequences of drug therapy in the elderly." View abstract/electronic edition; access limited to Brown University users, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3318308.
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Ashrafi, Koorosh. "Novel bioresponsive drug eluting microspheres to enhance chemoembolisation therapy." Thesis, University of Brighton, 2014. https://research.brighton.ac.uk/en/studentTheses/d72e0cce-8b99-4659-9b8d-c0e5a48da701.
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Drug eluting beads (DEB) are employed in the treatment of solid hypervascularised malignant tumours by a method called trans-arterial chemoembolisation (TACE). When the microcirculation to a tumour is blocked, oxygen levels decrease to critically low levels causing the tumour to become hypoxic. Hypoxic tumours are known to be chemoresistant and send out growth factor signals leading to angiogenesis and metastasis of tumour cells to other parts of the body. Commercially available DEB are unable to respond to the conditions of hypoxia and will continue to release drug at a constant rate via ionic exchange through the hydrogel. It is therefore recognised that an avenue for improvement would be the development of novel bioresponsive DEB that are able to react to the conditions of hypoxia to overcome chemoresistance associated with the tumour cells.
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LOGRIPPO, SERENA. "Dysphagia: daily concerns and formulative approaches for drug therapy." Doctoral thesis, Università degli Studi di Camerino, 2018. http://hdl.handle.net/11581/428648.
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This doctoral thesis aimed to argue about the specific subject of dysphagia and its relative concerns. Dysphagia is defined as the sensation of delayed passage of the bolus from the mouth to the stomach and issues regarding swallowing of drug therapy are going to be discussed and faced in this work. In fact, focus was mainly pointed on the difficulty of solid oral dosage forms deglutition and, on problems related to compounding and administration of drug therapy. Two model drugs were examined: pravastatin sodium and potassium canrenoate. Their diffuse prescription makes them two interesting molecules in order to optimize alternative dosage forms with respect to the solid one.
The pharmaceutical market offers a wide availability of dosage forms but solid ones are by far the most common due to some advantages that they have in terms of production, stability of the molecule, and costs. Sometimes, not all active molecules are formulated in the preferable form suitable to dysphagic people as well. Population with swallowing inability requires some specific arrangements to assume the prescribed drug therapy.
Compounding commercial dosage forms is not always possible, for example in case of gastro-enteric or controlled-release formulations. Nevertheless, the lack of awareness and proper background make errors happen in the several care settings (hospital, nursing homes, long-term care facilities) where dysphagic patients are admitted. Other problems may occur during manipulation process such as, for example, invaluable drug losses, active molecule instability, palatability decrease, cross-contamination among the drug powders crushed in the same device.
To overcome some issues related to drug intake in dysphagic people, the purpose of the work was to optimize compounding process in order to produce suitable dosage forms for this specific target population.
The work was organized in the following parts. After a general introduction of dysphagia issue, biopharmaceutics considerations concerning drug compounding were argued in the first part of the thesis.
In the second chapter, current clinical practice was dealt with. Whatever was daily performed in the hospital setting, for instance, tablet splitting to facilitate drug intake reducing tablet size, or inappropriate prescriptions of solid oral dosage forms when other therapeutic forms would be available, or occupation risks related to hospital workers during bedside compounding were discussed.
The third chapter of the work addressed the optimization of some dosage forms. Liquid dispersions of pravastatin sodium and potassium canrenoate were set up and enteral delivery via feeding tubes was analyzed for both of them. Pravastatin sodium was further studied to prepare a gelified form to replace tablet. Rheological and kinetic release profile studies were evaluated. The same statin was used to refine an orodispersible film able to disintegrate in the mouth after contact with saliva.
All these dosage forms, studied and tuned in the laboratory, might be able to replace commercial tablets. They might guarantee drug therapy to those who, due to their inability to swallow solid forms, would not have therapeutic alternative with the exception of extemporaneously and bedside produced preparations.
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Ward, Richard. "Targeting inositol monophosphatase in structure-based drug design." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289291.
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García, Díaz María. "Drug delivery in photodynamic therapy: From pharmaceutics to animal testing." Doctoral thesis, Universitat Ramon Llull, 2012. http://hdl.handle.net/10803/81987.
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S'ha estudiat el desenvolupament de fotosensibilitzadors i la seva formulació en teràpia fotodinàmica. S'han caracteritzat les propietats fotofísiques dels fotosensibilitzadors porficènics. S'han proposat diferents estratègies tals com la introducció de grups carboxilat en la perifèria o ions de metalls pesants en el nucli, per millorar el disseny de nous fotosensibilitzadors basats en el macrocicle porficènic.
Entre ells, el temocè (m-THPPo), el porficè anàleg a la temoporfina, mostra excel•lents propietats fotofísiques, fotoestabilitat i alta eficàcia fotodinàmica. A causa de la seva alta hidrofobicitat, s'ha desenvolupat una formulació liposomal per a l'administració in vitro i in vivo del temocè. m-THPPo/DPPC/DMPG (1:67.5:7.5 relació molar) té alta eficiència d'encapsulació mantenint les seves propietats tant fotofísiques com a biològiques. El temocè liposomal va exhibir l'eficàcia fotodinàmica in vitro més alta per molècula internalitzada, sent un sistema d'administració de fàrmacs eficaç per a una estratègia in vivo dirigida a les cèl•lules tumorals. El temocè encapsulat en micel•les de Cremophor EL va mostrar una mínima internalització cel•lular. Consistentment, la formulació micel•lar va mostrar millor la resposta in vivo quan s'utilitza en un règim vascular.
Amb la finalitat de minimitzar la internalització del fotosensibilitzador en les cèl•lules normals, es van proposar liposomes decorats amb lligands folat. Aquesta estratègia resulta en una internalització dues vegades major dels liposomes dirigits al receptor folat respecte a la corresponent formulació no específica.
Finalment, han estat explorats nous models cel•lulars in vitro per a l'optimització dels processos amb oxigen singlet. Els cultius cel•lulars en 3D reprodueixen l'heterogeneïtat d'oxigen i fotosensibilitzador que està present en els teixits reals, proporcionant informació molt útil per interpretar i predir el resultat de la teràpia fotodinàmica. També s'ha demostrat la capacitat de desactivació de l'oxigen singlet d'antioxidants en un model ex vivo de pell porcina.Se ha estudiado el desarrollo de fotosensibilizadores y su formulación en terapia fotodinámica. Se han caracterizado las propiedades fotofísicas de los fotosensibilizadores porficénicos. Se han propuesto diferentes estrategias tales como la introducción de grupos carboxilato en la periferia o iones de metales pesados en el núcleo, para mejorar el diseño de nuevos fotosensibilizadores basados en el macrociclo porficénico. Entre ellos, el temoceno (m-THPPo), el porficeno análogo a la temoporfina, muestra excelentes propiedades fotofísicas, fotoestabilidad y alta eficacia fotodinámica. Debido a su alta hidrofobicidad, se ha desarrollado una formulación liposomal para la administración in vitro e in vivo del temoceno. m-THPPo/DPPC/DMPG (1:67.5:7.5 relación molar) tiene alta eficiencia de encapsulación manteniendo sus propiedades tanto fotofísicas como biológicas. El temoceno liposomal exhibió la eficacia fotodinámica in vitro más alta por molécula internalizada, siendo un sistema de administración de fármacos eficaz para una estrategia in vivo dirigida a las células tumorales. El temoceno encapsulado en micelas de Cremophor EL mostró una mínima internalización celular. Consistentemente, la formulación micelar mostró mejor la respuesta in vivo cuando se utiliza en un régimen vascular. Con el fin de minimizar la internalización del fotosensibilizador en las células normales, se propusieron liposomas decorados con ligandos folato. Esta estrategia resulta en una internalización dos veces mayor de los liposomas dirigidos al receptor folato respecto a la correspondiente formulación no específica. Por último, han sido explorados nuevos modelos celulares in vitro para la optimización de los procesos con oxígeno singlete. Los cultivos celulares en 3D reproducen la heterogeneidad de oxígeno y fotosensibilizador que está presente en los tejidos reales, proporcionando información muy útil para interpretar y predecir el resultado de la terapia fotodinámica. También se ha demostrado la capacidad de desactivación del oxígeno singlete de antioxidantes en un modelo ex vivo de piel porcina.
The photosensitizer and formulation development in photodynamic therapy have been studied. They have been characterized the photophysical properties of new porphycene-based photosensitizers. Different strategies such as the introduction of carboxylate groups in the periphery or heavy metal ions in the core have been proposed for improving the design of novel photosensitizers based on the porphycene macrocycle. Among them, temocene (m-THPPo), the porphycene analogue to temoporfin, shows excellent photophysical properties, superior photostability and high photodynamic efficiency. Owing to its high hydrophobicity, a liposomal formulation has been developed for in vitro and in vivo administration of temocene. m-THPPo/DPPC/DMPG (1:67.5:7.5 molar ratio) yielded high encapsulation efficiency maintaining its photophysical and biological properties. Liposomal temocene exhibited the highest in vitro killing efficacy per uptaken molecule and they were an efficient drug delivery system for in vivo tumor cell targeting strategy. Temocene encapsulated in Cremophor EL micelles showed minimal cell internalization. Consistently, micellar formulation showed the best in vivo response when used in a vascular regime. In order to minimize the internalization of the photosensitizer in normal cells, liposomes decorated with folic acid ligands were proposed. This strategy leads to a 2-fold higher uptake of folate-targeted liposomes than the corresponding non-targeted formulation. Finally, new in vitro cellular models for a better optimization of singlet oxygen-involved processes were explored. 3D cellular cultures reproduced the oxygen and photosensitizer heterogeneity found in real tissues, providing useful information to interpret and predict the photodynamic therapy outcome. The singlet oxygen quenching ability of antioxidants in ex vivo porcine skin model has also been demonstrated.
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Webster, Amy Philomena. "Epigenetics of response to biologic drug therapy in rheumatoid arthritis." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/epigenetics-of-response-to-biologic-drug-therapy-in-rheumatoid-arthritis(d1518a5c-ef1c-4d8f-b210-8a2342139a45).html.
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Background: Rheumatoid arthritis (RA) is a common complex autoimmune disorder which is influenced by both genetic and environmental factors. While multiple factors that influence susceptibility to and outcome of disease have been identified there is still a large proportion of missing heritability and limited understanding of disease pathogenesis. In recent years, biologic drug therapies have advanced treatment of RA; however good disease control is achieved in just 30% of patients, making identification of predictors of treatment response important. One area of research which is yet to be explored in relation to treatment response, and requires further evaluation in RA susceptibility, is epigenetics. Epigenetics is the study of modifications of the DNA which can influence gene expression but do not alter genetic sequence, and the most commonly studied epigenetic phenomenon, to date, is DNA methylation. Objectives: To identify DNA methylation signatures predictive of treatment response to anti-TNF biologics, to explore the role of DNA methylation in RA susceptibility using disease discordant monozygotic (MZ) twins, and to assess the effect of cryopreservation of cells on DNA methylation. Methods: Genome-wide DNA methylation levels were measured using the HumanMethylation450 BeadChip in pre-treatment whole blood DNA samples from individuals who had extremely good or extremely poor response to the anti-TNF therapies, etanercept and adalimumab, and in MZ twins discordant for RA (n=79 pairs). I also compared genome-wide methylation in cells which had been cryopreserved with fresh cells, to investigate if this technique is suitable for epigenetic investigations. Results: I identified four methylation sites which were significantly related to response to etanercept at a false discovery rate of 5%, the most significantly differentially methylated of which maps to the LRPAP1 gene (p=1.46E-8). Indeed, four other sites at the same locus also showed evidence for differential methylation indicating that this represents a differentially methylated region. No sites were significantly associated with response to adalimumab after correction for multiple testing. I identified subtle differences in DNA methylation between RA discordant twins. Although these were not statistically significant following adjustment for cell composition, one of the most differentially methylated positions mapped to the ZNF74 gene (p=4.97E-6), and replicated a methylation difference identified in the largest previous epigenome-wide association study of RA cases and unrelated healthy controls. I found that cryopreservation of cells does not significantly alter the methylome, an important observation that will impact upon design of future studies. Conclusions: In the largest studies of DNA methylation in RA treatment response and RA discordant MZ twins to date, I identified significant differential methylation in etanercept response, but not adalimumab response, and found small differences in methylation in RA discordant MZ twins. I also concluded that cryopreservation does not significantly alter the methylome.
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Campbell, Michael, Mobeen Moslem, Preston Spriggel, and Terri Warholak. "Identifying Drug Therapy Problems Through Patient Consultation at Community Pharmacies." The University of Arizona, 2013. http://hdl.handle.net/10150/614231.
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Class of 2013 AbstractSpecific Aims: The objective of this quality improvement project is to evaluate if drug therapy problems in a community pharmacy setting can be identified via patient counseling at the time of prescription pick up. The central hypothesis of the project is that patient consultation will aid in identifying drug therapy problems and reduce the amount of negative effects posed by these problems. Methods: This project will assess data obtained through a medication therapy intervention report utilized in multiple community pharmacy environments in Arizona. Any consultation provided to a patient by a pharmacist or pharmacy intern regarding a new or transferred prescription will be eligible for data collection. The primary dependent variable is the number of drug therapy problems identified during consultation. Drug therapy problems will be assessed via expert opinion to identify the potential negative impact they may have posed to patients. Data analysis will involve the frequency and type of drug therapy problems identified during data collection. Main Results: A total of 1305 prescriptions were screened during the data collection period. A total of 29 drug therapy problems were identified upon patient consultation. This yielded a 2.2% drug therapy problem occurrence during data collection. The most commonly occurring drug therapy problem involved a patient drug allergy or sensitivity issue. Conclusion: Future research is warranted on the effects that drug therapy problems have on patients and the healthcare system. This project is descriptive in nature and may not be applicable to every community pharmacy in Arizona.
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Qin, Yiru. "Graphene Quantum Dots-Based Drug Delivery for Ovarian Cancer Therapy." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6358.
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Ovarian cancer, one of the most dreadful malignancies of the female reproductive system, poses a lethal threat to women worldwide. In this dissertation, the objective was to introduce a novel type of graphene quantum dots (GQDs) based nano-sized drug delivery systems (DDS) for ovarian cancer treatment. As a starting point, the facile synthesis method of the GQDs was established. Subsequently, the targeting ligand,folic acid (FA), was conjugated to GQDs. Next, a FDA approved chemotherapeutic drug, Doxorubicin (DOX), was loaded to form the GQDs-FA-DOX nano-conjugation as the DDS. Moreover, the uptake profile and anti-cancer effect of the GQDs-FA-DOX were validated in ovarian cancer cells. Finally, the immunotoxicity of GQDs and its mechanism were investigated and elucidated. Taken together, the findings described in this dissertation provide a novel and powerful strategy of targeted treatment for ovarian cancer.
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Rynes, Kristina N. "Demand-withdraw interaction in family therapy for adolescent drug abuse." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/194526.
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Demand-withdraw interaction is a pattern of communication in which one person demands change from another who withdraws. In the treatment domain, evidence of parallel demand-withdraw processes comes from a study of couple therapy for alcoholic men, where wife-demand/husband-withdraw interaction predicted poor response to a high-demand intervention (Shoham et al., 1998). The current study extends this parallelprocess idea to family therapy for substance-using adolescents by examining whether adolescents entrenched in parent-demand/adolescent-withdraw interaction are less likely to engage in treatment and more likely to use drugs post-treatment when counselors pressure them to change. Participants were 91 families who received ≥ 4 sessions of Brief Strategic Family Therapy (BSFT; Szapocznik et al., 2003) in a multi-site clinical trial on adolescent drug abuse and an additional non-engagement sample of 21 families who completed ≤ 2 sessions. Before randomization, families completed videotaped family interaction tasks from which trained observers coded parent-demand/adolescent-withdraw. Another team of raters coded therapists’ demands during an early and (for most cases) a later BSFT session, while a third team rated quality of BSFT. The main dependent variable was a composite index of adolescent substance use based on monthly self-reports and urine drug screens over 12 months. A matched-sample examination of sessions attended (≤ 2 vs. ≥ 4) revealed no effect of early-session therapist demand on engagement. However, multi-level models partially supported the main hypothesis: adolescents high in parent-demand/adolescent withdraw who received high-quality BSFT from relatively non-demanding therapists used fewer drugs during and after treatment than other adolescent participants. Furthermore, as therapist demand on high PD/AW adolescents increased, youth substance use also increased. Results suggest that attending to parallel demand-withdraw processes in parent/adolescent and therapist/adolescent dyads may be useful in family therapy for substance-using adolescents. Replicating ineffective parent behavior within the therapeutic system may undermine the prospect of decreased adolescent drug use outcomes.
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Tang, Jingjie. "Innovative imaging systems and novel drug candidates for cancer therapy." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4021.
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Le cancer est l'une des principales causes de décès dans le monde et reste une maladie difficile à traiter du fait des difficultés de pronostic, du développement rapide de métastases et de la résistance aux médicaments. Il en résulte une forte demande en méthodologies d'imagerie innovantes pour le diagnostic précoce et précis ainsi qu’en nouveaux agents anticancéreux possédant de nouveaux mécanismes pour surmonter la résistance aux médicaments. Le but de mon projet de recherche de doctorat était donc de contribuer à cet objectif.La première partie de ma thèse de doctorat a porté sur la création de systèmes sensibles et précis d'imagerie pour la détection de tumeurs cancéreuses en utilisant une nanotechnologie novatrice permettant la délivrance des agents d'imagerie spécifiquement dans les lésions tumorales. Nous avons conçu de nouveaux dendrimères amphiphiles pour assurer le transport de différents agents d'imagerie pour les imageries PET/SPECT, par résonance magnétique et par fluorescence optique. Ces systèmes d'imagerie ont été préparés soit par encapsulation de petites sondes d'imagerie à l'intérieur de nanomicelles dendritiques ou par fonctionnalisation de la surface hydrophile ou de la queue hydrophobe du dendrimère. La deuxième partie a eu pour objectif de développer de nouveaux agents anticancéreux possédant nouveaux mécanismes d’action et une meilleure activité antitumorale. A cet effet, nous avons conçu une série de nucléosides arylvinyltriazoles par réaction oxydante de Heck, ce qui nous a permis d'obtenir les composés désirés pourtant difficiles à synthétiser avec un très large éventail de substrats et une stéréosélectivité uniqueCancer is one of the leading causes of death in the world, and remains a difficult disease to treat because of poor prognosis, rapid tumor metastasis and drug resistance. Therefore, innovative imaging modalities for early and precise diagnosis as well as new anticancer drug candidates with novel mechanisms to overcome drug resistance are in high demand. The aim of my PhD research project was to contribute to this goal.The first part of my PhD thesis was focused on establishing sensitive and precise imaging systems for cancer detection using innovative nanotechnology to deliver imaging agents specifically into tumor lesions. We designed and constructed novel amphiphilic dendrimers to carry different imaging agents for PET/SPECT imaging, magnetic resonance imaging and optical fluorescence imaging. These innovative imaging systems were prepared by either encapsulation of small imaging probes within the dendrimer nanomicelles, or functionalization of the dendrimer hydrophilic surface or hydrophobic tail. The second part of my PhD program aimed to develop new anticancer drug candidates with novel mechanisms for better anticancer activity. Therefore, we designed and synthesized a series of challenging arylvinyltriazole nucleosides via the oxidative Heck reaction, which allowed us to obtain the desired compounds with excellent substrate scope and unique stereoselectivity
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Tang, Jingjie. "Innovative imaging systems and novel drug candidates for cancer therapy." Electronic Thesis or Diss., Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4021.
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Le cancer est l'une des principales causes de décès dans le monde et reste une maladie difficile à traiter du fait des difficultés de pronostic, du développement rapide de métastases et de la résistance aux médicaments. Il en résulte une forte demande en méthodologies d'imagerie innovantes pour le diagnostic précoce et précis ainsi qu’en nouveaux agents anticancéreux possédant de nouveaux mécanismes pour surmonter la résistance aux médicaments. Le but de mon projet de recherche de doctorat était donc de contribuer à cet objectif.La première partie de ma thèse de doctorat a porté sur la création de systèmes sensibles et précis d'imagerie pour la détection de tumeurs cancéreuses en utilisant une nanotechnologie novatrice permettant la délivrance des agents d'imagerie spécifiquement dans les lésions tumorales. Nous avons conçu de nouveaux dendrimères amphiphiles pour assurer le transport de différents agents d'imagerie pour les imageries PET/SPECT, par résonance magnétique et par fluorescence optique. Ces systèmes d'imagerie ont été préparés soit par encapsulation de petites sondes d'imagerie à l'intérieur de nanomicelles dendritiques ou par fonctionnalisation de la surface hydrophile ou de la queue hydrophobe du dendrimère. La deuxième partie a eu pour objectif de développer de nouveaux agents anticancéreux possédant nouveaux mécanismes d’action et une meilleure activité antitumorale. A cet effet, nous avons conçu une série de nucléosides arylvinyltriazoles par réaction oxydante de Heck, ce qui nous a permis d'obtenir les composés désirés pourtant difficiles à synthétiser avec un très large éventail de substrats et une stéréosélectivité uniqueCancer is one of the leading causes of death in the world, and remains a difficult disease to treat because of poor prognosis, rapid tumor metastasis and drug resistance. Therefore, innovative imaging modalities for early and precise diagnosis as well as new anticancer drug candidates with novel mechanisms to overcome drug resistance are in high demand. The aim of my PhD research project was to contribute to this goal.The first part of my PhD thesis was focused on establishing sensitive and precise imaging systems for cancer detection using innovative nanotechnology to deliver imaging agents specifically into tumor lesions. We designed and constructed novel amphiphilic dendrimers to carry different imaging agents for PET/SPECT imaging, magnetic resonance imaging and optical fluorescence imaging. These innovative imaging systems were prepared by either encapsulation of small imaging probes within the dendrimer nanomicelles, or functionalization of the dendrimer hydrophilic surface or hydrophobic tail. The second part of my PhD program aimed to develop new anticancer drug candidates with novel mechanisms for better anticancer activity. Therefore, we designed and synthesized a series of challenging arylvinyltriazole nucleosides via the oxidative Heck reaction, which allowed us to obtain the desired compounds with excellent substrate scope and unique stereoselectivity
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Bernard, Julia M., and M. Klein. "Teenage Drug Use." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/5802.
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Almoyad, Muhammad. "Synergism from combination of targeted therapy and phytochemicals in colorectal cancer." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18161.
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Colorectal cancer is the second most common cancer in women and third in men, accounting for 9.7 % of all cancers incidence. Oxaliplatin is a platinum-based anticancer drug used typically in combination with folinic acid and 5-fluorouracil for treatment against colorectal cancer. However, numerous side effects such as nausea and vomiting, GI toxicity, anaemia, immunodeficiency, ototoxicity, nephrotoxicity, and neurotoxicity are associated with its use. These can be decreased by lowering dose of oxaliplatin. Phytochemicals that can act as antioxidants have been used by people in treatment against cancer throughout human history because of their low toxicity and the ease in availability. Besides providing protection against cancer, they can also kill cancer cells. Studies show that chemopreventive agents would boost activity of anticancer drugs and thus improve treatment outcome. In this study, resveratrol, thymoquinone, capsaicin and quercetin were applied to four human colorectal cancer cell lines HT-29, Caco-2, Lim-1215 and Lim-2405 in combination with platinum drugs cisplatin and oxaliplatin using three sequences of administration (0/0 h, 0/4 h and 4/0 h). Activity of compounds alone and in combination were determined using MTT reduction assay. Combination index was used as a measure of combined drug action. Studies on cellular accumulation, platinumDNA binding, DNA damage and proteomics were carried out to obtain mechanistic insights. In HT-29 cell line all sequences of administration produced antagonism at lower concentration (ED50). In Caco-2 cell line, bolus combination of cisplatin with resveratrol was found to produce moderate synergistic effect at all concentrations. In Lim-2405 cell line, combination of cisplatin with quercetin was found to produce most synergistic outcome. As applied to oxaliplatin, its combination with quercetin was found to produce most synergistic outcomes in Caco-2 cell line. Combination of oxaliplatin and capsaicin was most synergistic in Lim-2405 cell line. Results on PtDNA binding showed that synergistic effect was associated with higher platinumDNA binding. In proteomics study, 16 proteins belonging to different functional groupings were found to undergo changes in expression as a result of treatment with synergistic combinations.
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Yu, Wei. "Central pain after spinal cord injury : experimental studies with special emphasis on pharmacological treatment /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3156-9/.
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Phiboonbanakit, Danabhand. "The interrelationship between intracellular thymidine and thymidine analogues phosphorylation." Thesis, University of Liverpool, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484288.
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Cheng, Yu. "Gold Nanoparticles as Drug Delivery Vectors for Photodynamic Therapy of Cancers." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1301503263.
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Näsman, Margareta. "Effects of anti-neoplastic therapy on tooth and bone formation : clinical and experimental studies /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3282-4/.
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Escolà, Jané Anna. "Somatostatin analogues as drug delivery systems for receptor-targeted cancer therapy." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663804.
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Somatostatin (SST or SRIF14) is a peptidic hormone secreted throughout the central nervous system and in the gastrointestinal tract which has anti-secretory, anti-proliferative and anti-angiogenic effects. Although its administration as a drug is effective in certain conditions, its therapeutic use is limited by its short plasma half-life (< 3 min), the broad spectrum of biological responses and the lack of selectivity over its receptors (SSTRs).
In order to obtain more stable and selective analogues we have incorporated both non-natural electron-rich and electron-poor aromatic amino acids at key positions of the native sequence to overcome the above-mentioned drawbacks. In this regard, we have obtained different analogues which have been studied by NMR obtaining the structures of the major set of conformations. Their binding profile and half-lives have also been determined. Among all the analogues, one stood out due to its half-life of around 40 h, the highest one known for a SRIF14 analogue. Furthermore, it displayed a major set of conformations in solution and high selectivity towards SSTR2.
In recent years, receptor-targeted cancer therapy has gained interest as certain receptors are overexpressed in cancer cells. This is the case of SSTRs in endocrine tumours. On this subject, we have coupled different molecules at the N-terminal part of the previously mentioned analogue. The first one was a chromophore which enabled us to follow the internalisation of the analogue inside CHO-K1 wild type (WT) and CHO-K1 SSTR2-overexpressing (ST) cell lines which turned to be far more better in ST than in WT. In light of these findings, we decided to go one step further and test this analogue as a drug delivery system thus coupling it to a colour-changing chromophore (green: bonded to the peptide, blue: when released). As before, both the internalisation and the drug release was better in ST than in WT. Last step was to test the analogue as a p38α inhibitor by coupling the inhibitor directly at the N-terminal part. As for the other assays, the inhibition of p-Hsp27 (p38α downstream target) was better in ST than in WT which was attributed to a better internalisation of the analogue.La somatostatina (SST o SRIF14) es una hormona peptídica secretada por el sistema nervioso central y el tracto gastrointestinal que tiene efectos anti-secretores, anti-proliferativos y anti-angiogénicos. Aunque su administración como fármaco es eficaz en ciertas condiciones, su uso terapéutico está limitado por su corta vida media plasmática (<3 min), el amplio espectro de respuestas biológicas y la falta de selectividad entre sus receptores. Con el fin de obtener análogos más estables y selectivos, hemos incorporado aminoácidos aromáticos no naturales ricos y pobres en electrones en posiciones clave de la secuencia nativa para superar dichos inconvenientes. Así, se obtuvieron diferentes análogos que fueron estudiados por RMN obteniendo la estructura de sus conformaciones mayoritarias. También se determinó su perfil de unión a los receptores y sus vidas medias. Entre los análogos, uno destacó por tener una vida media de 40 h, la más alta conocida para un análogo de 14 aminoácidos. Además, mostró un conjunto de conformaciones en solución parecido y una gran selectividad para SSTR2. Recientemente, la terapia contra el cáncer dirigida a receptores ha ganado interés ya que ciertos receptores están sobre-expresados en las células cancerosas. Este es el caso de los receptores de somatostatina en tumores endocrinos. Así, acoplamos diferentes moléculas en la parte N-terminal del análogo mencionado anteriormente. La primera fue un cromóforo que nos permitió seguir la internalización del análogo en dos líneas celulares: CHO-K1 de tipo salvaje (WT) y CHO-K1 con SSTR2 sobre-expresado (ST); dicha internalización fue mucho mejor en ST que en WT. Al ver estos resultados prometedores, fuimos un paso más allá y probamos el análogo cómo sistema de liberación de fármacos, acoplándolo a un cromóforo que cambia de color (verde: unido al péptido, azul: cuando se libera). Cómo antes, tanto la internalización como la liberación fueron mejores en ST que en WT. El último paso fue probar el análogo como inhibidor de p38α acoplando el inhibidor directamente en la parte N-terminal. Cómo en los ensayos anteriores, la inhibición de p-Hsp27 (diana downstream de p38α) fue mejor en ST que en WT, lo que se atribuyó a una mejor internalización del análogo en ST.
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Heij, Sebastiaan de. "Development of a micromachined vaporiser for use in inhalation drug therapy /." [S.l. : s.n.], 2000. http://www.gbv.de/dms/bs/toc/330852108.pdf.
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Nusair, Yanal M. H. "Clinical outcome measures of a non-drug preventive therapy for migraine." Thesis, Queen's University Belfast, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326286.
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Donnelly, R. F. "Bioadhesive drug delivery systems for photodynamic therapy of vulval intraepithelial neoplasia." Thesis, Queen's University Belfast, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398149.
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Riaz, Muhammad Kashif. "Peptide functionalized drug delivery system for an efficient lung cancer therapy." HKBU Institutional Repository, 2019. https://repository.hkbu.edu.hk/etd_oa/609.
Full textAbstract:
Lung cancer has a high incidence rate globally and the leading cause of cancer related mortalities. In 2018, lung cancer has been estimated to cause 1.76 million deaths worldwide (18.33% of total cancer mortalities). In Hong Kong lung cancer has been a leading cause of cancer related deaths, and in 2016 caused 3780 deaths (26.6% of total cancer mortalities). Non-small cell lung cancer (NSCLC) is the major (~85%) lung cancer type, and five-year survival rate for lung cancer has estimated to be 18%. Thus, an efficient lung cancer treatment with lesser adverse effects is need of the hour. In this connection, active targeting of overexpressed receptors at lung tumor site with a ligand functionalized drug delivery system is the current approach, and pulmonary administration could augment chemotherapeutic effect of the drug through localized administration, minimizing the off-target effects by retention of the drug in lungs.Quercetin (QR), a natural flavonoid present in edible fruits and vegetables possess anticancer activity i.e. inhibits lung cancer growth. However, the application of QR in lung cancer therapy has been restricted by various factors i.e. low water solubility (2.15 µg/ml at room temperature), low bioavailability and rapid plasma clearance. To overcome the issues, we have formulated various QR-loaded liposomes surface functionalized with transferrin receptor (TFR) targeting peptides i.e. T7 (HAIYPRH) and T12 (THRPPMWSPVWP) in two research projects with active targeting ability, prolonged circulation time, and sustained release behavior for lung cancer specific QR delivery. In first research project, T7 targeted liposomes with different peptide densities i.e. 0.5%, 1% and 2% and QR-lip (non-targeted) were formulated. TFRs are over expressed (~100 folds) in various cancers including lung cancer and have low expression in most normal cells. T7 surface-functionalized liposomes (2% T7-QR-lip) demonstrated significantly enhanced cytotoxicity (~3-folds), cellular-uptake, S-phase cell cycle arrest and apoptosis in A549 cells. However, in MRC-5 (normal-lung fibroblast) cells no significant difference was observed after treatment with T7-QR-lip and QR-lip in cytotoxicity and cellular uptake studies. In tumor spheroid penetration and inhibition studies, T7 targeted liposomes showed deeper penetration and pronounced inhibition. In vivo biodistribution study via pulmonary administration of T7-DiR-lip has demonstrated liposomes accumulation in the lungs and sustained-release behavior upto 96h. Further, T7-QR-lip significantly enhanced anticancer activity of QR and life-span of orthotopic lung-tumor bearing mice (**p < 0.01, compared with control) via pulmonary administration. In second research project, T12 surface-functionalized liposomes with 0.5%, 1% and 2% T12 peptide densities and QR-lip have been formulated with ~95 % encapsulation efficiency. In vitro drug release study showed sustained release of QR from T12-QR-lip and QR-lip. In vitro experiments showed A549 cells treatment with 2% T12-QR-lip enhanced cellular-uptake, in vitro cytotoxicity, induced apoptosis and S-phase cell cycle arrest due to TFR mediated endocytosis. No significant variation has been observed in cellular-uptake and cytotoxicity after MRC-5 cells were treated with T12-QR-lip and QR-lip. Further, T12-Cou6-lip showed significantly deeper penetration i.e. 120 µm in 3D lung tumor-spheroids. Biodistribution study showed retention of T12-DiR-lip and DiR-lip mainly in the lungs upto 96h after pulmonary administration, as compared to free DiR. Pulmonary administration of T12-QR-lip showed the strongest tumor growth inhibition and survival time of orthotopic lung tumor implanted mice without any systemic toxicity as compared to QR-lip and free-QR. In summary, in vitro and in vivo results of the two research projects suggest that surface functionalization of the liposomes with TFR targeting peptides i.e. T7 and T12 is a promising approach for lung cancer therapy through active targeting and receptor mediated endocytosis of QR at lung tumor site. Moreover, T7 and T12 functionalized liposomes provides a potential drug delivery system for a range of anticancer drugs to enhance their therapeutic efficacy by localized i.e. pulmonary administration and targeted delivery.
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Hernández, Teruel Adrián. "Smart drug delivery systems designed to improve Inflammatory Bowel Disease therapy." Doctoral thesis, Universitat Politècnica de València, 2019. http://hdl.handle.net/10251/129863.
Full textAbstract:
[ES] La presente tesis doctoral titulada "Sistemas de liberacio'n controlada de fa'rmacos diseñados para mejorar el tratamiento de Enfermedad Inflamatoria Intestinal" se centra en el diseño, preparación, caracterización y evaluación in vivo de distintos sistemas de liberación controlada de fármacos en colon (CDDS, por sus siglas en inglés) utilizando como soporte micropartículas de silice mesoporosa, funcionalizadas con puertas moleculares.
En conclusión, los estudios realizados demuestran que los materiales de silice mesoporosa, en combinación con puertas moleculares sensibles a estímulos específicos, tienen un gran potencial para el desarrollo de nuevos sistemas de liberación controlada de fármacos en el colon, dirigidos a mejorar el arsenal terapéutico disponible para el tratamiento de EII. La posibilidad de adaptar o personalizar la carga y las puertas moleculares hace que estos soportes de sílice mesoporosa sean una opción interesante para el desarrollo de nuevos sistemas de liberación controlada de fármacos en diferentes aplicaciones biomédicas. Finalmente, esperamos que los resultados obtenidos en esta tesis doctoral sirvan de inspiración para el desarrollo de sistemas de liberación controlada de fármacos innovadores y cada vez más inteligentes, para su aplicación tanto en medicina como en otras áreas.[CAT] La present tesi doctoral titulada "Sistemes d'alliberament controlat de farmacs dissenyats per a millorar el tractament de Malaltia Inflamatoria Intestinal" se centra en el disseny, preparacio, caracteritzacio i avaluacio in vivo de diferents sistemes d'alliberament controlat de farmacs en colon (*CDDS, per les seues sigles en angles) utilitzant com a suport microparticules de si'lice mesoporosa, funcionalitzades amb portes moleculars. En conclusio, els estudis realitzats demostren que els materials de si'lice mesoporosa, en combinacio amb portes moleculars sensibles a estimuls especifics, tenen un gran potencial per al desenvolupament de nous sistemes d'alliberament controlat de farmacs en el colon, dirigits a millorar l'arsenal terapeutic disponible per al tractament de MII. La possibilitat d'adaptar o personalitzar la carrega i les portes moleculars, fa que aquests suports de silice mesoporosa siguen una opcio interessant per al desenvolupament de nous sistemes d'alliberacio controlada de farmacs en diferents aplicacions biomediques. Finalment, esperem que els resultats obtinguts en aquesta tesi doctoral servisquen d'inspiracio per al desenvolupament de sistemes d'alliberament controlat de farmacs innovadors i cada vegada mes intel·ligents, per a la seua aplicacio tant en medicina com en altres arees.
[EN] This PhD thesis entitled "Smart drug delivery systems designed to improve Inflammatory Bowel Disease therapy" is focused on the design, synthesis, characterization and in vivo evaluation of several Colon Drug Delivery Systems (CDDS) using hybrid mesoporous silica microparticles as scaffolds containing molecular gates. In conclusion, the studies shown in this Thesis demonstrate that mesoporous silica materials in combination with responsive molecular gates have great potential in the design and preparation of new CDDS to improve the therapeutic options available for IBD. The possibility to adapt the cargo and the molecular gate makes mesoporous silica support especially appealing for similar controlled drug delivery applications in the biomedical field. We hope that the obtained results could inspire the development of new innovative smart drug delivery systems in this or other fields.
We thank the Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235-C2-2-R (MINECO/FEDER)) and the Generalitat Valenciana (project PROMETEOII/2014/047) for support. AHT thanks to the Spanish MEC for his FPU grant. We thank the Generalitat Valenciana (Project PROMETEO2018/024)
Hernández Teruel, A. (2019). Smart drug delivery systems designed to improve Inflammatory Bowel Disease therapy [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/129863
TESIS
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Madadi, Ardekani Sara. "CARBON NANOMATERIALS DERIVED FROM ORGANIC SOURCES FOR DRUG DELIVERY AND THERAPY." Thesis, The University of Sydney, 2019. http://hdl.handle.net/2123/20998.
Full textAbstract:
Remotely triggered drug delivery using nanoparticles is an area of great interest for targeted therapy to fight cancer. We developed photoresponsive nanoparticles to remotely initiate the release of doxorubicin (DOX) to 3D cultured human breast cancer cells (MCF-7) via NIR two-photon excitation (TPE) using carbon nanomaterials (CNMs). The drug loading capacity of CND-P was measured to be 0.98 w/w with the ability to release DOX via two-photon excitation (TPE). The biocompatible CNMs showed 88% cell viability at concentrations as high as 1100 μg/mL. The combined chemo and photothermal therapeutic effect of the DOX-loaded CNMs resulted in the death of 78% of the MCF-7 cells compared to 59% with DOX alone. Apart from extracellular pathogens, a common theme in the persistence of microbial infections involves intracellular survival of microbial pathogens within their host cells. To destroy such a recalcitrant pathogen, an intracellular infection of the cultured epithelial cell-line H413 with the periodontal pathogen Porphyromonas gingivalis (P. gingivalis) was used. The conjugated CNMs were rapidly internalized into the cultured cells, reaching almost 90% uptake within 3 hours of the challenge, resulting in significantly increased inhibition of intracellular P. gingivalis compared to metronidazole alone. Conjugated CNMs and the drug doxorubicin (DOX) developed to release DOX from the surface of CNMs into cell nuclei with the use of ultrasound (ULS) as a trigger. The amino-acid derived green-emitting CNMs with high quantum yield (40%) showed excellent drug loading efficiency (97% w/w). The on-demand drug release was validated by taking advantage of the fluorescent properties of the CNMs using both confocal laser scanning microscopy and time-correlated single-photon counting techniques. Exposure of conjugated CNMs to 180 s of ULS enhanced its efficiency by 26.32 % compared to DOX alone.
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Bowyer, Cressida Jane. "Hypoxia as a target for drug combination therapy of liver cancer." Thesis, University of Brighton, 2012. https://research.brighton.ac.uk/en/studentTheses/c90ec816-21e3-402e-9451-2be249b0e162.
Full textAbstract:
Oxygen is a requirement for almost all living organisms and adaptations to oxygen shortage are essential for surviving periods of oxygen deprivation, known as hypoxia. Cells have evolved a range of mechanisms which increase the supply of oxygen and facilitate metabolic alterations that enable the cell and the organism to maintain functionality under hypoxic conditions. Hypoxia is a hallmark of solid tumours and is associated with increased malignancy and mortality in hepatocellular carcinoma (HCC). Transarterial chemoembolisation therapy (TACE) using doxorubicin is the current standard of care for intermediate HCC, although response rates are poor. Drug eluting bead transarterial chemoembolisation (DEB-TACE) shows improved response rates over TACE. More recently, rapamycin has come under scrutiny as an effective therapy against HCC. Embolisation therapies have been shown to induce hypoxia in HCC, leading to the escape of hypoxia-adapted cancer cells from therapy. The principal transcription factor which orchestrates responses to hypoxia is hypoxia inducible factor 1 (HIF-1). Laboratory and clinical evidence support the hypothesis that HIF-1 activity contributes to cancer progression and increased mortality. Targeting HIF-1 therefore presents an opportunity for improving outcomes of cancer therapy. A hypoxic model of HCC was established, and used to characterise the responses of the cell line HepG2 to chemotherapeutic agents in both normoxic and hypoxic conditions. Firstly, the time and concentration dependent effects of doxorubicin, rapamycin and both drugs in combination on the viability of HepG2 cells cultured under both normoxic and hypoxic conditions were investigated. SDS-PAGE and Western Blotting was then used to evaluate the responses of HIF-1α, NFkB, S6K and Akt expression to doxorubicin, rapamycin and both drugs in combination in cells cultured under both normoxic and hypoxic conditions. Finally, the anti-tumour effects of doxorubicin, rapamycin and both drugs in combination were investigated in vivo using an ectopic xenograft murine model of HCC. The in vitro evidence presented in this thesis demonstrates that a concentration of doxorubicin relevant to clinical concentrations following DEB-TACE effectively inhibits the viability of both normoxic and hypoxic liver cancer cells. Also presented is in vitro evidence that low dose rapamycin inhibits the viability of both normoxic, and to a lesser extent, hypoxic liver cancer cells. The addition of low dose rapamycin to doxorubicin was consistently observed to have an additive effect on the inhibition of cell viability. Protein analysis demonstrated that low dose rapamycin inhibits the hypoxia stimulated accumulation of HIF-1α, as does high dose doxorubicin. However, inhibition of HIF-1α was attenuated when the two drugs were used in combination. Cytotoxic effects are not, therefore, wholly dependent on inhibition of HIF-1α. Inhibition of HIF-1α by each drug alone appears to be due to different mechanisms. This study also showed in vivo that combinations of doxorubicin DEB-TACE with either rapamycin DEB-TACE or oral rapamycin are more effective than either treatment alone at reducing tumour burden in a mouse model of HCC. Two clinical trials are now underway to investigate the combination of doxorubicin DEB-TACE and low dose oral rapamycin to treat HCC.
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ANGELINI, GIUSEPPE. "DRUG-MEDIATED NFIX INHIBITION AS A NEW THERAPY FOR MUSCULAR DYSTROPHIES." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/841278.
Full textAbstract:
Le distrofie muscolari (DM) sono un gruppo di miopatie monogeniche ancora incurabili, caratterizzate da una progressiva degenerazione del muscolo scheletrico, da complicazioni respiratorie e cardiache, e morte prematura. Le miofibre distrofiche sono molto fragili a causa di mutazioni nel Complesso Distrofina-Glicoproteina (DGC), che fornisce un supporto fisico alla contrazione muscolare. Per via di queste mutazioni, nei muscoli distrofici si verificano cicli continui di degenerazione/rigenerazione delle miofibre, i quali causano progressivamente un esaurimento delle cellule satelliti, le cellule staminali muscolari scheletriche, e la perdita del tessuto muscolare scheletrico.
I topi distrofici geneticamente privi del fattore di trascrizione Nfix, cruciale per il passaggio dalla miogenesi embrionale a quella fetale, presentano miglioramenti morfologici e funzionali della malattia. Ciò è dovuto al rallentamento della rigenerazione muscolare e ad uno cambiamento fenotipico delle miofibre verso un metabolismo più ossidative in assenza di Nfix.
Recentemente, nel nostro laboratorio abbiamo dimostrato che la via di segnalazione delle MAPK (MEK/ERK) modula positivamente i livelli di Nfix sia nei miooblasti fetali in vitro che nei feti in vivo, suggerendo una possibile via verso un'inibizione farmacologica indiretta di Nfix in un contesto distrofico.
In questo progetto di ricerca, abbiamo dimostrato che tale regolazione è conservata anche nei mioblasti postnatali. Infatti, il trattamento cronico di topi Sgca null adulti con due MEK-inibitori usati in clinica, Trametinib e Selumetinib, ogni giorno per 14 giorni tramite sonda gastrica orale, provoca una diminuzione dei livelli delle proteine pERK e Nfix nei muscoli scheletrici distrofici. L'espressione del gene Nfix nel muscolo trattato non cambia, indicando il coinvolgimento di meccanismi di regolazione post-traduzionali piuttosto che trascrizionali. Questa riduzione di Nfix non è ancora sufficiente tuttavia a garantire un miglioramento morfologico dei muscoli distrofici, i quali presentano miofibre più piccole, necrosi più alta e, inaspettatamente, delle calcificazioni in seguito a trattamento con alte dosi dei farmaci. Ciononostante, i muscoli trattati con Trametinib e Selumetinib presentano un numero più alto di miofibre con un metabolismo ossidativo, il quale protegge dai danni distrofici.
Il nostro studio dimostra che Nfix è modulato dal pathway di MEK/ERK nei muscoli distrofici postnatali in vivo, facendo luce sulla rete di regolazione alla base di questo fattore di trascrizione così importante nelle MD. Combinare la somministrazione dei MEK-inibitori con altri farmaci e/o un approccio di nutrigenomica da poco sviluppato nel nostro laboratorio, che agisce sulle calcificazioni, potrebbe portare a miglioramenti nel protocollo di trattamento, ponendo le basi ad un approccio combinato per affrontare tali malattie così eterogenee.Muscular Dystrophies (MDs) are still incurable monogenic myopathies characterized by progressive degeneration of skeletal muscle, respiratory and cardiac complications, and premature death. Dystrophic myofibers are highly fragile, due to mutations in the Dystrophin-Glycoprotein Complex (DGC), which provides a physical support to muscle contraction. In dystrophic muscles, chronic cycles of degeneration/regeneration of myofibers occur, progressively leading to an exhaustion of satellite cells, the skeletal muscle stem cells (MuSCs), and to the loss of skeletal muscle tissue. Dystrophic mice lacking the transcription factor Nfix, crucial for the switch from embryonic to fetal myogenesis, display morphological and functional improvements of the disease, due to the slowing down of muscle regeneration and to a shift towards more oxidative myofibers. Recently, we demonstrated that the MAPK (MEK/ERK) signaling pathway positively regulates the Nfix protein levels both in fetal myoblasts in vitro and in fetuses in vivo, bringing out the idea of an indirect pharmacological inhibition of Nfix in a dystrophic context. In this research project, we demonstrate that this regulation is also conserved in postnatal myoblasts. Chronic treatment of adult Sgca null mice with two FDA-approved MEK-inhibitors, Trametinib and Selumetinib, every day for 14 days by oral gavage, causes a decrease of pERK and Nfix protein levels in dystrophic skeletal muscles. The Nfix gene expression in treated muscle does not change, indicating the involvement of post-translational rather than transcriptional mechanisms of regulation. This reduction of Nfix is nevertheless not sufficient to improve the histology of dystrophic muscles, which display smaller myofibers, higher necrosis, and, unexpectedly, calcification at high drugs dosages. However, Trametinib- and Selumetinib-treated muscles exhibit more myofibers with an oxidative metabolism, which is known to protect from dystrophic damage. Our study provides a proof-of-concept that Nfix is modulated by the MEK/ERK pathway in postnatal dystrophic muscles in vivo, unraveling the regulatory network behind this crucial transcription factor in MDs. Combining the MEK-inhibitor administration with other drugs and/or a type of diet acting on calcifications might improve the treatment, setting the stage for a combined approach to face such heterogeneous diseases.
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MAUCERI, MATTEO. "New Targeted Molecules for the Therapy of Ovarian Cancer." Doctoral thesis, Università degli Studi di Trieste, 2022. http://hdl.handle.net/11368/3031106.
Full textAbstract:
Patients with high-grade serous ovarian cancer (HGSOC), the most aggressive epithelial ovarian cancer (EOC) subtype, have a 5-year survival rate of about 93% when diagnosed at an early stage, but it drops to 30-40% when diagnosed in the advanced stage. HGSOC aggressiveness is mainly caused by the late diagnosis (51% stage III, 29% stage IV) when the tumor has already spread in the peritoneal cavity. PIN1 is a unique peptidyl-prolyl isomerase that targets the phosphorylated Ser/Thr(Pro) motifs to regulate several key proteins in different signaling pathways. Pin1 is overexpressed in several cancer types and it regulates more than 40 oncogenes and 20 tumor suppressors. Many functions are modulated through PIN1-mediated isomerization such as cell cycle progression, cellular proliferation, invasion, migration, and apoptosis. Downregulation of Pin1 decreases tumor progression. Recently, Pin1 was shown to be overexpressed in ovarian cancer (OC) which, together with the high number of interactions with other proteins, makes Pin1 a promising target for HGSOC. The aim of this work is to investigate the effects of the PIN1 inhibitor VS10 on cancer cell lines and to find the molecular signaling pathways in which Pin1 is involved. Migration, mesothelial clearance assay, and the effects on spheroid formation and preformed spheroids were studied to better understand the effects on the metastatic process. Furthermore, in order to clarify the molecular mechanism that triggers the cytotoxicity induced by Pin1 inhibition in several OC cell lines, silencing Pin1 has been demonstrated to be associated with Ser473pAkt dephosphorylation by Western Blot (WB) analysis. Additionally, cell viability and colony-forming assays showed that Akt overexpression rescued the lethal phenotype due to Pin1 knockdown in OVCAR3 and KURAMOCHI OC cell lines. Among PIN1 inhibitors, All-trans retinoic acid (ATRA), a drug in clinic for the treatment of acute promyelocytic leukemia, has been demonstrated to be active on PIN1. Our group developed many PIN1 inhibitors including VS10, a non-covalent and selective molecule, which is active in killing cancer cells. ATRA and VS10 have been combined with first- and second-line chemotherapy drugs to treat SKOV3 cell line whether these drug combinations could work synergistically to improve current therapy. This drug combination screening showed that Doxorubicin and Caelyx act in synergy with both VS10 and ATRA. This drug combination was studied in 5 sensible and 2 OC cell lines resistant to cisplatin treatment. These results candidate Pin1 as a promising new molecular target for HGSOC patients' therapy.Patients with high-grade serous ovarian cancer (HGSOC), the most aggressive epithelial ovarian cancer (EOC) subtype, have a 5-year survival rate of about 93% when diagnosed at an early stage, but it drops to 30-40% when diagnosed in the advanced stage. HGSOC aggressiveness is mainly caused by the late diagnosis (51% stage III, 29% stage IV) when the tumor has already spread in the peritoneal cavity. PIN1 is a unique peptidyl-prolyl isomerase that targets the phosphorylated Ser/Thr(Pro) motifs to regulate several key proteins in different signaling pathways. Pin1 is overexpressed in several cancer types and it regulates more than 40 oncogenes and 20 tumor suppressors. Many functions are modulated through PIN1-mediated isomerization such as cell cycle progression, cellular proliferation, invasion, migration, and apoptosis. Downregulation of Pin1 decreases tumor progression. Recently, Pin1 was shown to be overexpressed in ovarian cancer (OC) which, together with the high number of interactions with other proteins, makes Pin1 a promising target for HGSOC. The aim of this work is to investigate the effects of the PIN1 inhibitor VS10 on cancer cell lines and to find the molecular signaling pathways in which Pin1 is involved. Migration, mesothelial clearance assay, and the effects on spheroid formation and preformed spheroids were studied to better understand the effects on the metastatic process. Furthermore, in order to clarify the molecular mechanism that triggers the cytotoxicity induced by Pin1 inhibition in several OC cell lines, silencing Pin1 has been demonstrated to be associated with Ser473pAkt dephosphorylation by Western Blot (WB) analysis. Additionally, cell viability and colony-forming assays showed that Akt overexpression rescued the lethal phenotype due to Pin1 knockdown in OVCAR3 and KURAMOCHI OC cell lines. Among PIN1 inhibitors, All-trans retinoic acid (ATRA), a drug in clinic for the treatment of acute promyelocytic leukemia, has been demonstrated to be active on PIN1. Our group developed many PIN1 inhibitors including VS10, a non-covalent and selective molecule, which is active in killing cancer cells. ATRA and VS10 have been combined with first- and second-line chemotherapy drugs to treat SKOV3 cell line whether these drug combinations could work synergistically to improve current therapy. This drug combination screening showed that Doxorubicin and Caelyx act in synergy with both VS10 and ATRA. This drug combination was studied in 5 sensible and 2 OC cell lines resistant to cisplatin treatment. These results candidate Pin1 as a promising new molecular target for HGSOC patients' therapy.
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Ketchem, Shannon, Katie Prosser, Christine Colon, Diana Heiman, Kelly Covert, and David Stewart. "Thrombocytopenia Risk with Valproic Acid Therapy." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/asrf/2020/presentations/47.
Full textAbstract:
Valproic acid (Depakote) is an antiepileptic drug approved for the treatment of bipolar disorder, migraine prophylaxis, and seizure disorders. While the exact mechanism is still unknown, thrombocytopenia, defined as platelet counts < 150,000/uL, has been reported secondary to Depakote treatment. The frequency of Depakote-induced thrombocytopenia varies greatly, with reported rates ranging from 5 to 54%. This adverse effect is dose-dependent and possible risk factors include lower baseline platelet counts, female gender, and high VPA serum concentrations.Our team came across two patient cases where thrombocytopenia during Depakote therapy was observed. Patient information was gathered through electronic medical records. The first patient was a 65-year-old male who was started on 500 mg Depakote ER three tablets at night for bipolar affective disorder. After several months on this dose, the patient’s platelets decreased to 59 X 103per microliter. One month after the drug was discontinued, the platelets recovered to 160 X 103per microliter. The second patient was a 57-year-old woman who had two occurrences of thrombocytopenia while on Depakote. The patient was started on Depakote for a seizure disorder. She was later admitted for symptomatic bradycardia, hypotension, and concern for thrombocytopenia. Her Depakote dose was decreased from 500 mg three times a day to twice a day. Approximately 5 weeks later, she presented to the emergency room for decreased arousal and hypotension. She was again found to have thrombocytopenia with a platelet count of 28 X 103per microliter with a Depakote level of 101 mcg/mL. The team discovered she had been receiving Depakote 500 mg three times a day following discharge from her last admission, not the reduced dose prescribed. On day four of admission, her platelets had not improved and the Depakote dose was decreased further to 250 mg twice daily. After Depakote was discontinued her platelets gradually improved and returned to normal after four days, the eighth day of admission. Utilizing the Naranjo adverse drug reaction probability scale, the first patient case had a probable reliability that this adverse reaction was due to Depakote, while the second patient case had a definite reliability.These cases illustrate the potential for thrombocytopenia secondary to Valproic acid use. Although this adverse event isn’t well understood, these cases add to the evidence that it can occur. Recognition of this reaction is important and clinicians should monitor hematologic labs, including platelets, for patients receiving Valproic acid.
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Parrish, A. G. "Cost-effectiveness of nebulised ipratropium as adjunctive therapy in acute asthma." Master's thesis, University of Cape Town, 1993. http://hdl.handle.net/11427/24972.
Full textAbstract:
Aim: To determine whether the addition of nebulised ipratropium to the therapy of acute asthma leads to a cost-effective reduction in the mean duration of admission and time to maximum peak expiratory flow rate (PEFR). Method: Patients with an admission diagnosis of acute asthma were studied in a double-blind, placebo-controlled trial in which they received a standard therapeutic regimen of continuous intravenous aminophylline, 4-hourly fenoterol nebulisation, intravenous methylprednisolone 125mg 12-hourly, and, every four hours, either nebulised saline placebo or ipratropium bromide 500mcg in 3ml saline. Data on age, gender, initial and maximum PEFR, time to maximum PEFR, and duration of hospital stay was collected from the hospital record after discharge. Statistical techniques: 2-way contingency tables for categorical variables, 1-way ANOVA for treatment effects, and life-table analysis of the time till discharge. Results: Records of 279 of the 400 patients entered in the study were suitable for analysis after excluding re-admissions, non-asthmatics and incomplete records. Baseline comparisons of age and severity on presentation showed no significant differences. The trial group did not differ significantly from the control group with respect to either time to PEFR (respectively 21.11 hours (SD 14.3) versus 22.89 (SD 15.82)) or duration of admission (5.02 (SD 3.65) versus 5.38 (SD 3.13) 6-hour units). In a sub-group of patients (n=155) demonstrating more than 100% improvement in PEFR, the time to maximum PEFR was significantly shorter in the ipratropium group (20.35 hours SD 12.4) versus 25.20 hours (SD 17.0); p= 0.045). Conclusion: The addition of ipratropium bromide to a standard treatment regimen for acute asthma reduced the time to achieve maximum PEFR in a sub-group of patients with markedly reversible airflow limitation. Overall, however, the addition did not prove cost-effective.
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Sheerin, Ian G., and n/a. "Consequences of drug use and benefits of methadone maintenance therapy for Maori and non-Maori injecting drug users." University of Otago. Christchurch School of Medicine & Health Sciences, 2005. http://adt.otago.ac.nz./public/adt-NZDU20070502.142602.
Full textAbstract:
The consequences of drug use and benefits of methadone maintenance therapy (MMT) were investigated in a random sample of Maori and non- Maori injecting drug users in Christchurch, Aotearoa New Zealand. Eighty- five injecting drug users (IDUs) who had been on MMT for a mean time of 57 months were interviewed and followed up over an average 18 month period.
Markov models were used to model cohorts of IDUs, changes in their health states and the effects of MMT and anti-viral therapy on morbidity and mortality. The savings in life from reductions in drug overdoses were used as the main outcome measure in cost-effectiveness analysis. Cost-utility and cost-benefit analysis were also used to provide additional information on the costs and outcomes of treatment. Comparisons were made between: (a) MMT alone; (b) MMT provided with conventional combination therapy for hepatitis C virus (HCV); and (c) MMT provided with anti-viral therapy with pegylated interferon.
The monetary costs of drug use and benefits of MMT were similar for Maori and non-Maori. However, Markov modelling indicated that MMT is associated with greater savings in life for Maori than for non-Maori. Further, Maori IDUs identified the main personal costs of drug use as being loss of their children and loss of marriage or partners.
Large reductions in use of opioids and benzodiazipines were reported at interview, compared with before starting MMT. The participants also reported large reductions in crime and stabilisation of their lifestyles. Improvements in the general health of IDUs om MMT were reported. However, 89% were positive for HCV infection, which was identified as the major physical health problem affecting IDUs in New Zealand. Few IDUs had received anti-viral therapy for HCV infections, despite having stabilised on MMT. This study investigated the benefits of providing anti-viral therapy for HCV to all patients meeting treatment criteria.
The cost-effectiveness of MMT alone was estimated at $25,397 per life year saved (LYS) for non- Maori men and $25,035 for non-Maori women IDUs (costs and benefits discounted at 3%). The incremental effects of providing anti-viral therapy for HCV to all eligible patients were to save extra years of life, as well as to involve additional costs. The net effect was that anti-viral therapy could be provided, at a similar level of cost-effectiveness, to all patients who meet HCV treatment criteria. Cost-effectiveness could be improved if IDUs could be stabilised on MMT five years earlier at an average age of 26 instead of the current age of 31 years. The cost-effectiveness of treatment with pegylated interferon was similar to that for conventional combination therapy because there were incremental savings in life as well as increased treatment costs.
Costs per LYS were estimated to be lower for Maori than for non-Maori, reflecting ethnic differences in mortality. Sensitivity analysis revealed that provision of MMT with anti-viral treatment remained cost-effective under varying assumptions of mortality, disease progression and compliance with treatment.
the main problems that were not improved during MMT were continuing use of tobacco and cannabis, low participation in paid employment, only three participants had received specific treatment for their HCV infections.
Cost-benefit analysis using a conservative approach showed a ratio of the benefits to the costs of MMT of 8:1. Benefits were demonstrated in terms of large reductions in crime. Benefit to cost ratios were similar for the different policy examined, as well as for both Maori and non-Maori IDUs.
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Xu, Leyuan. "Engineering of Polyamidoamine Dendrimers for Cancer Therapy." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3773.
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Dendrimers are a class of polymers with a highly branched, three-dimensional architecture comprised of an initiator core, several interior layers of repeating units, and multiple active surface terminal groups. Dendrimers have been recognized as the most versatile compositionally and structurally controlled nanoscale building blocks for drug and gene delivery. Polyamidoamine (PAMAM) dendrimers have been most investigated because of their unique structures and properties. Polycationic PAMAM dendrimers form compacted polyplexes with nucleic acids at physiological pH, holding great potential for gene delivery.
Folate receptor (FRα) is expressed at very low levels in normal tissues but expressed at high levels in cancers in order to meet the folate demand of rapidly dividing cells under low folate conditions. Our primary aim was to investigate folic acid (FA)-conjugated PAMAM dendrimer generation 4 (G4) conjugates (G4-FA) for targeted gene delivery. The in vitro cellular uptake and transfection efficiency of G4-FA conjugates and G4-FA/DNA polyplexes were investigated in Chapter 4. It was found the cellular uptake of G4-FA conjugates and G4-FA/DNA polyplexes was in a FR-dependent manner. Free FA competitively inhibited the cellular uptake of G4-FA conjugates and G4-FA/DNA polyplexes. G4-FA/DNA polyplexes were preferentially taken up by FR-positive HN12 cells but not FR-negative U87 cells. In contrast, the cellular uptake of G4 dendrimers and G4/DNA polyplexes was non-selective via absorptive endocytosis. G4-FA conjugates significantly enhanced cytocompatibility and transfection efficiency compared to G4 dendrimers. This work demonstrates that G4-FA conjugates allow FR-targeted gene delivery, reduce cytotoxicity, and enhance gene transfection efficiency.
The in vivo biodistribution of G4-FA conjugates and anticancer efficacy of G4-FA/siRNA polyplexes were investigated in Chapter 5. Vascular endothelial growth factor A (VEGFA) is one of the major regulators of angiogenesis, essential for the tumor development. It was found G4-FA/siVEGFA polyplexes significantly knocked down VEGFA mRNA expression and protein release in HN12 cells. In the HN12 tumor-bearing nude mice, G4-FA conjugates were preferentially taken up by the tumor and retained in the tumor for at least 21 days following intratumoral (i.t.) administration. Two-dose i.t. administration of G4-FA/siVEGFA polyplexes significantly inhibited tumor growth by lowering tumor angiogenesis. In contrast, two-dose i.t. administration of G4/siVEGFA polyplexes caused severe skin lesion, presumably as a result of local toxicity. Taken together, this work shows great potential for the use of G4-FA conjugates in targeted gene delivery and cancer gene therapy.
We also explored polyanionic PAMAM dendrimer G4.5 as the underlying carrier to carry camptothecin (CPT) for glioblastoma multiforme therapyin Chapter 6. "Click" chemistry was applied to improve polymer-drug coupling reaction efficiency. The CPT-conjugate displayed a dose-dependent toxicity with an IC50 of 5 μM, a 185-fold increase relative to free CPT, presumably as a result of slow release. The conjugated CPT resulted in G2/M arrest and cell death while the dendrimer itself had little to no toxicity. This work indicates highly efficient "click" chemistry allows for the synthesis of multifunctional dendrimers for sustained drug delivery.
Immobilizing PAMAM dendrimers to the cell surface may represent an innovative method of enhancing cell surface loading capacity to deliver therapeutic and imaging agents. In Chapter 7, macrophage RAW264.7 (RAW) was hybridized with PAMAM dendrimer G4.0 (DEN) on the basis of bioorthogonal chemistry. Efficient and selective cell surface immobilization of dendrimers was confirmed by confocal microscopy. It was found the viability and motility of RAW-DEN hybrids remained the same as untreated RAW cells. Furthermore, azido sugar and dendrimer treatment showed no effect on intracellular AKT, p38, and NFκB (p65) signaling, indicating that the hybridization process neither induced cell stress response nor altered normal signaling. This work shows the feasibility of applying bioorthogonal chemistry to create cell-nanoparticle hybrids and demonstrates the noninvasiveness of this cell surface engineering approach.
In summary, these studies indicate surface-modification of PAMAM dendrimer G4 with FA can effectively target at FR-positive cells and subsequently enhance in vitro transfection efficiency and in vivo gene delivery. G4-FA conjugates may serve as a versatile targeted gene delivery carrier potentially for cancer gene therapy. PAMAM dendrimers G4.5 may serve as a drug delivery carrier for the controlled release of chemotherapeutics. The immune cell-dendrimer hybrids via bioorthogonal chemistry may serve as an innovative drug and gene delivery carrier potentially for cancer chemotherapy. Taken together, engineering of PAMAM dendrimers may advance anticancer drug and gene delivery.
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Man, Kwun-wai Dede, and 文冠慧. "Oleanolic acid delivery using biodegradable nanoparticles for cancer therapy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2015. http://hdl.handle.net/10722/208550.
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