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Keesling, James Richard. "An evaluation of the drugs crime nexus, legalization of drugs, drug enforcement, and drug treatment rehabilitation." CSUSB ScholarWorks, 2000. https://scholarworks.lib.csusb.edu/etd-project/1697.
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Law enforcement agencies are faced with the problem of how to reduce crime in the most economical method possible without violating the law. Since drug offenders also engage in a disproportionate amount of non-drug crime, then drug enforcement is considered as an acceptable general crime control method. Unfortuantely, this is an expensive option because incarcerating offenders is both costly and ony a short-term solution to the problem. A review of existing research examining the prior criminal histories of drug offenders compared to their previous involvement in violent and property crime is conducted to evaluate this relationship.
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Apps, MIchael Garry. "Platinum anticancer drugs and drug delivery systems." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/14409.
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In this thesis two different ways to improve platinum-based chemotherapy were investigated. The first was through the use of a new slow release clay-based drug delivery vehicle and the second through the design and synthesis of novel dinuclear platinum complexes. For the clay-based drug delivery research, the platinum anticancer complex [(1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)] chloride, PHENSS, was loaded into montmorillonite (MMT) clay. The PHENSS was found to be incompletely burst released from the MMT. The MMT also had a negative effect on the in vitro cytotoxicity of PHENSS in the human breast cancer cell lines MCF-7 and MDA-MB-231. Overall the results demonstrate that MMT is not a suitable slow release vehicle for PHENSS. For the dinuclear platinum complex synthesis research, new bispyridine-based bridging ligands were synthesised using an amide coupling reaction. The bridging ligands were then reacted with transplatin to yield the dinuclear platinum complexes. The platinum complexes have potential application as anticancer agents and the synthetic method can be modified to produce other multinuclear complexes.
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Yeh, Teng-Kuang. "Pharmacokinetics of anti-aids and anti-cancer drugs : implications on drug delivery and drug interaction /." The Ohio State University, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=osu148654688938101.
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Mannheimer, Buster. "Drug-related problems with special emphasis on drug-drug interactions." Stockholm : Department of Clinical Science and Education, Karolinska Institutet, 2009. http://diss.kib.ki.se/2009/978-91-7409-602-6/.
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Carroll, Steven M. McGuire Marvin H. "The economics of the drug war : effective federal policy or missed opportunity? /." Monterey, Calif. : Springfield, Va. : Naval Postgraduate School ; Available from National Technical Information Service, 2002. http://library.nps.navy.mil/uhtbin/hyperion-image/02Jun%5FCarroll%5FMcGuire.pdf.
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Osorio, Javier. "Hobbes on drugs| Understanding drug violence in Mexico." Thesis, University of Notre Dame, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3738644.
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This dissertation analyzes the unprecedented eruption of organized criminal violence in Mexico. To understand the dynamics of drug violence, this dissertation addresses three questions. What explains the onset of the war on drugs in Mexico? Once the conflict starts, why does drug violence escalate so rapidly? And lastly, why is there subnational variation in the concentration of violence?
Based on a game theoretic model, the central argument indicates that democratization erodes the peaceful configurations between the state and criminal organizations and motivates authorities to fight crime, thus triggering a wave of violence between the state and organized criminals and among rival criminal groups fighting to control strategic territories. In this account, state action is not neutral: law enforcement against a criminal group generates the opportunity for a rival criminal organization to invade its territory, thus leading to violent interactions among rival criminal groups. These dynamics of violence tend to concentrate in territories favorable for the reception, production and distribution of drugs. In this way, the disrupting effect of law enforcement unleashes a massive wave of violence of all-against-all resembling a Hobbesian state of war.
To test the observable implications of the theory, the empirical assessment relies on a novel database of geo-referenced daily event data at municipal level providing detailed information on who did what to whom, when and where in the Mexican war on drugs. This database covers all municipalities of the country between 2000 and 2010, thus comprising about 9.8 million observations. The creation of this fine-grained database required the development of Eventus ID, a novel software for automated coding of event data from text in Spanish. The statistical assessment relies on quasi-experimental identification strategies and time-series analysis to overcome problems of causal inference associated with analyzing the distinct - yet overlapping - processes of violence between government authorities and organized criminals and among rival criminal groups. In addition, the statistical analysis is complemented with insights from fieldwork and historical process tracing. Results provide strong support for the empirical implications derived from the theoretical model.
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Raedisch, Steffen. "Drug transport and drug-drug interactions at the blood-brain barrier." Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2005162/.
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Membrane transporters are increasingly recognised as being important in determining drug pharmacokinetics at whole body, organ, and cellular levels. At the blood-‐brain barrier (BBB), membrane transporters determine the passage of drugs into and out of the brain. About 30 % of all patients are classed as non-‐responders for both epilepsy and schizophrenia. Drug transporters from the adenosine 5'-‐ triphosphate (ATP)-‐binding cassette (ABC) transporter family or from the solute carrier (SLC) superfamily may contribute to these drug resistant phenotypes but most have received limited attention. Treatment response to carbamazepine (CBZ) has been associated with genetic polymorphisms in ABCC2, particularly -‐24C>T, c.1249G>A, and c.3972C>T. However, the results have been conflicting and inconclusive amongst the different studies. A functional and clinical analysis was undertaken to investigate the impact of ABCC2 on CBZ treatment response. In vitro, no ABCC2-‐mediated CBZ transport could be observed in efflux assays with an ABCC2-‐transfected human fibrosarcoma cell line (Rht14-‐10) and a dog kidney cell line (MDCKII). In addition, uptake into inside-‐out vesicles derived from the Rht14-‐10 cell line was negative. Clinical analysis of patients from the SANAD (Standard and New Antiepileptic Drugs) trial (assessing the clinical end-‐points time to first seizure (n = 229) and time to 12-‐month remission (n = 134)) did not show any significant associations between the three ABCC2 gene polymorphisms, -‐24C>T, c.1249G>A, c.3972C>T, and clinical outcomes. In an attempt to identify currently unrecognised human drug transporters with potential relevance to epilepsy and schizophrenia, screening of transport of CBZ, lamotrigine (LTG), topiramate (TPM), levetiracetam, valproate, phenytoin, and clozapine (CLP) was undertaken using an immortalised human brain endothelial cell line (hCMEC/D3) as an in vitro model of the BBB. Accumulation of TPM was significantly enhanced by 44-‐53 % in the presence of the typical ABCC efflux transporter inhibitors MK571 and montelukast. Furthermore, CLP uptake was significantly reduced by 94 % and 83 % in the presence of the typical organic cation transporter inhibitors prazosin and verapamil, respectively. CLP uptake into the hCMEC/D3 cell line followed classical Michaelis-‐Menten kinetics with Vmax of 3288 (pmol/million cells)/min and Km of 35.93 μM. To identify the exact underlying transporters involved in TPM efflux and CLP uptake, both functional siRNA screening was undertaken and transport was investigated in transfected cell lines. None of the known functional ABCC transporters were shown to transport TPM. In addition, none of the expressed and functionally characterised organic cation transporters from the SLC22A family, as well as transporters from the SLC6A, SLC28A, and SLC29A families, had an effect on CLP accumulation. LTG has recently been identified as a substrate for SLC22A1 (OCT1). Interaction with the human immunodeficiency virus protease inhibitors lopinavir/ritonavir and the antipsychotic CLP was therefore investigated. At clinically relevant concentrations, lopinavir was found to significantly reduce SLC22A1-‐mediated uptake of LTG by 39 %. In addition, CLP was a potent inhibitor of SLC22A1-‐mediated LTG uptake yielding an IC50 of 1.8 μM. Similarly low IC50 values were obtained with primary human hepatocytes from two patients (IC50 = 7.9 μM and IC50 = 3.9 μM, respectively) and the hCMEC/D3 cell line (IC50 = 2.0 μM). The clinical consequences of these observations will require further in vivo pharmacokinetic and epidemiological research. In conclusion, the results presented in this thesis demonstrate that membrane transporters can be involved in the passage of AEDs and antipsychotics across the BBB and other membrane barriers. However, currently available in vitro methods proved to be insufficient to identify and characterise the underlying transporters involved and to further evaluate the impact on treatment efficacy. The development of large-‐scale functional screening methodologies will be crucial for a more systematic and comprehensive understanding of drug transport processes involved in determining access of drugs to the central nervous system. This will help in improving drug efficacy and drug safety, allow prediction of drug-‐drug interactions, and eventually allowed a more personalised approach to prescribing in diseases such as epilepsy and schizophrenia.
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Sikri, Vineet Mitra Ashim K. "Efflux transporters mediated drug-drug interaction." Diss., UMK access, 2004.
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Thesis (M.S.)--School of Pharmacy. University of Missouri--Kansas City, 2004."A thesis in pharmaceutical sciences." Typescript. Advisor: Ashim K. Mitra. Vita. Title from "catalog record" of the print edition Description based on contents viewed Feb 28, 2006. Includes bibliographical references (leaves 94-107). Online version of the print edition.
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Hughes, Caitlin Elizabeth. "Overcoming obstacles to reform : making and shaping drug policy in contemporary Portugal and Australia /." Connect to thesis, 2006. http://eprints.unimelb.edu.au/archive/00003215.
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McGuffog, Ingrid Diana. "Drug Use and Drug Control Policy: Evaluating the Impact of Precursor Regulation on Drug User Behaviour." Thesis, Griffith University, 2013. http://hdl.handle.net/10072/366750.
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Controlling the availability of illicit drugs and their use is an exemplar of a wicked problem. Reducing the scale of the illicit drugs market through suppressing supply has proven extremely difficult. A recent systematic review of studies by Cunningham and colleagues who have produced a series of research papers examining the impact of precursor regulations on various methamphetamine outcomes in North America, argue this research represents the most compelling evidence to date that ‘precursor regulations, or indeed any supply control strategy, can have significant impacts on the retail market for illicit drugs’. The review of this work concludes that the question for future research is ‘not so much whether precursor regulations work, but which regulations work best and in what context’; this is the starting point for my research.
The market for methamphetamine is entrenched, broad and dynamic and represents an important criminological and public health problem in Australia. Within Australia the production of methamphetamine has been concentrated in Queensland and that state government has responded by developing a coercive regulatory framework which co-opts pharmacies into a partnership with drug law enforcement that is aimed at preventing the diversion of licit precursor chemicals to the illicit market for manufacture into methamphetamine. In 2005, the Queensland Pharmacy Guild in partnership with the Queensland Police Service developed an electronic medication recording system Project STOP, - which is a real-time web based database used by police to track and apprehend ‘pseudo runners’ - to facilitate adherence to the compulsory requirements of recording and reporting sales of pseudoephedrine placed upon them by both health regulations and the criminal law. In my thesis, I refer to the family of innovations (legislative, policy and technological interventions) underpinning the police–pharmacy partnership as Third Party Policing (TPP).Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Criminology and Criminal Justice
Arts, Education and Law
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Fairbrother, Sally M. "Evading drug efflux with drug-binding peptides." Thesis, University of Manchester, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.512210.
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The efflux of drugs, particularly multi-drug resistant (MDR) drugs, by transporters such as P-glycoprotein provides an additional hurdle to achieving high levels of drug bioavailability. The aim of this project was to investigate drug-binding peptides as potential delivery tools, which might circumvent drug efflux by transporters such as Pglycoprotein. Popkov et 01 1998 reported a number of phage-displayed peptides (I Omers), which bound to doxorubicin. A literature search was carried out and several other potential drug-binding sequences were identified. Peptides were synthesised and then screened for drug-binding and their effect on drug interactions with P-glycoprotein. Due to the small and hydrophobic nature of the drug and peptide molecules, both homogeneous and heterogeneous drug-peptide binding assays were investigated. Drugpeptide binding was identified in one sequence using circular dichroism, size exclusion HPLC, equilibrium dialysis and a new biosensor, the Farfield AnalightBi0200. Competition assays using the fluorophores rhodamine 123 and calcein-AM suggested that MDR drugs formed complexes with these fluorophores. Drug-peptide aggregates were also identified by particle sizing, using photon correlation spectroscopy. Drug-P-glycoprotein interactions were investigated using a cell-based competition assays, cytotoxicity and MDCK cell monolayer transport studies. All the potential drug-binding peptide sequences were screened using a calcein-AM competition assay in PGP over-expressing cells (CHO CHRC5), whereby calcein-AM and drug (± peptide) compete to interact with P-glycoprotein. Only the Popkov-reported sequences were found to reduce drug-P-glycoprotein interactions. However, these sequences did not enhance the cytotoxicity of doxorubicin or vinblastine (cytotoxic P-glycoprotein substrates) in Caco-2 or CHO CHRC5 cells. MDCK monolayer studies found the peptide to have a slight but not significant effect on 3H vinblastine basal to apical transport. This difference may be due to greater sensitivity of the calcein AM compared to the monolayer transport assay. With a view to enhancing the delivery properties of the drug-binding peptides, new sequences containing cell-penetrating motifs were synthesised. The Penetratin sequence was synthesised in tandem to a drug-binding peptide sequence, whilst the Simian virus 40 motif was added to the peptide using a linker. Both these peptides gave similar results in the calcein-AM competition assay as the drug-binding peptide alone. The ability of the peptides to penetrate cell membranes was tested using a calcein-liposome leakage assay. Both the new sequences were slightly lytic, but complete liposome lysis particularly resulted when tamoxifen was added. Interestingly, a similar result was achieved with the drug-binding peptide sequence alone. Some drug-binding peptides appear to affect the behaviour of P-glycoprotein in suspended-cell transport models, when assayed by calcein-AM. However, the interaction between drugs and peptides in other cell-based models appears more complex.
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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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CHIARAPPA, GIANLUCA. "Drug nanocrystals in drug delivery and pharmacokinetics." Doctoral thesis, Università degli Studi di Trieste, 2018. http://hdl.handle.net/11368/2917681.
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As the oral route has always been the simplest and most appreciated way to administer drugs, the increasing number of new active drugs with very low solubility in water become a serious issue for the effectiveness of new medicinal specialties. Thus far, the best solution to this issue seems to be nanonization, i.e. the production of drugs as nanocrystals, which, by dramatically increasing crystal surface-volume ratio, reduces drug melting temperature with a relevant increase of drug solubility. Owing to experimental difficulties – presence of impurities, polymorphic forms, and Ostwald ripening phenomenon, i.e. the growth of the larger crystals at the expense of the smaller ones during dissolution – the determination of drugs solubility as a function of their dimension may be achieved only by a theoretical and numerical route. For these motives, the nanocrystals melting process was modeled from a thermodynamic point of view for the spheric, cylindrical, and parallelepiped-shaped geometry, by subsequently implementing the obtained mathematical model in Fortran programming language and numerically solving the written equations. The results obtained from the conducted studies are comparable to those deriving from molecular dynamics simulations.
Being thermodynamically unstable, however, nanocrystals recrystallize unless they are trapped inside stabilizing carriers such as, for instance, polymeric matrices. Thus, controlled release pharmaceutical systems, constituted by an active principle and a physically or chemically reticulated polymer, were considered. The influence of viscoelastic properties of polymeric networks on drug release was, hence, evaluated by developing an ad hoc mathematical model. The numerical solution with Gauss-Seidel’s method of the model partial differential equations system was seeked with an implicit scheme based on the control volumes strategy, by implementing that in Fortran programming language. One of the most interesting aspects of the developed model consists in the possibility of measuring its various parameters by means of different experimental techniques such as, for instance, rheology, low-field NMR, and release tests.
After deepening the importance of crystals shape selected to model organic drugs solubility and evaluating the influence of viscoelastic properties on the drug release from polymeric networks, the creation of a physiologically-oriented mathematical model, able to study the in vivo drug release, drug absorption, distribution, metabolism, and elimination (ADME) with particular attention to the evaluation of drug bioavailability increase related to the use of drug nanocrystals loaded into polymeric networks, was pursued. The mathematical model, constituted by a system of ordinary and partial differential equations, was implemented in Fortran programming language. This model allows comparing different formulations of the same drug or the same formulation for different drugs, evaluating effect of different doses, mean sizes and distribution of particles, and of drug solid states, i.e. amorphous, nanocrystalline, and macrocrystalline. One of the most important results of this study is the quantitative evaluation of the interaction between release kinetics and the subsequent ADME processes. Indeed, the proposed model demonstrates that the in vivo release kinetics may result different from the in vitro one owing to the effect of living tissues. In conclusion, the present model may be take into consideration and further developed as a useful tool for designing different oral release systems.
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Rosenbaum, Erik. "Optical characterization of potential drugs and drug delivery systems." Doctoral thesis, Umeå universitet, Kemiska institutionen, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-40177.
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This Thesis is a characterization study on substances having potency as drugs as well as on a lipid based drug-delivery matrix. The optical properties of newly synthesized molecules with proven pilicide properties have been characterized with several spectroscopic methods. These methods include optical absorption and fluorescence as well as time-resolved fluorescence. Upon covalently linking compounds with high quantum yields of fluorescence to specific parts of the pilicide, the biological impact was found to increase for some of the derivatives. Furthermore, by expanding the aromatic part of the pilicide molecule, a significant increase in the inherent fluorescence was obtained. The S0-S1 absorption band for these molecules was found to originate from an impure electronic transition, vibronically promoted by intensity borrowing from higher electronic states. Included in this Thesis is the measurement of how deeply some in this class of newly synthesized molecules become situated when placed inside ganglioside GM1 micelles, and how the molecules’ reorientation is affected. By means of radiation-less energy transfer, it was shown that the molecules place themselves close to the hydrophobic-hydrophilic interface inside the GM1 micelles. As a consequence they are exposed to a densely packed environment, which inhibits the free tumbling of the molecule. This restricted tumbling could be measured by means of time-resolved depolarization experiments. The release of drug-like fluorescent molecules is investigated from a lipid mixture, which upon equilibrium with water forms a mixture of inverted hexagonal and cubic phases. The lipid matrix displayed an extended release over the course of weeks, in vitro, for molecules having a large variation in hydrophobicity.
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Attardo, Giorgio G. (Giorgio Giovanni). "Drug design and synthesis of novel heteroanthracycline antitumor drugs." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74641.
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Novel heteroanthracycline antitumor drugs were designed based on structure activity relationship studies and known mechanisms of drug action. Their preparation required the development of a general synthetic approach.After extensive studies, three methodologies were developed for the general synthetic plan. The first method involved photoenolisation of 2,5-dimethoxybenzaldehyde and SO$ sb2$ entrapment of the o-quinodimethane to give 4,7-dimethoxy-1-hydroxy-1,3-dihydrobenzo(2,3-c) thiophene-2,2-dioxide. This compound served as a general intermediate towards the synthesis of several heteroanthracyclinones. It could be reduced to the oxathiin-2-oxide derivative which thermally extruded SO$ sb2$ to yield the o-quinodimethane. Reentrapment of this latter intermediate with various glyoxalates gave key isochroman derivatives. The second method is an improvement over the first. Isochromandiones with a C-1 hydroxyl functionality were prepared from oxidative demethylation of 1-hydroxyisochromans. These were obtained after acid hydrolysis of the coupling products between epoxides and the cuprate of 2,5-dimethoxy-6-methylbenzaldehydedioxane acetal. The third method involved a sequential cycloaddition routine with two o-quinodimethanes.
By combining newly developed techniques with known methods, a general synthetic plan was developed. Consequently, the total synthesis of six tetracyclic structural hybrids of the naphthoquinone(2,3-c) pyranyl class of antibiotics was accomplished; along with the total synthesis of (R) and (S) 1-(4$ sp prime$-O-p-nitrobenzoyl-N-trifluoroacetyldaunosamine)-$ 1,3$-dihydrothioxantho(2,3-c) thiophene-2,2-dioxide, p-nitrobenzyl(5,12-dihydroxy-3,4-dihydrothioxantho(2,3-c) and (3,2-c) pyran-3-yl)formate, and eight novel heteroanthracyclines with the 5,12-dioxo-2,3,5,12-tetrahydroanthraceno(2,3-c) pyranyl backbone. The diastereomeric mixture of (1$ sp prime$S, 1R, 3S) and (1$ sp prime$S, 1S, 3R) methyl(11-hydroxy-1-$(2 sp prime,3 sp prime,6 sp prime $-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-$5,12 $-dioxo-3,4,5,12-tetrahydroanthraceno(2,3-c) pyran-3-yl) formate was found to possess equipotent antileukemic activity to doxorubicin with no cross resistance.
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Hill, John C. "DRUMMING AWAY DRUGS: AN INNOVATIVE ALTERNATIVE TOWARDS DRUG REHABILITATION." UKnowledge, 2014. http://uknowledge.uky.edu/cld_etds/14.
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Drug use poses a serious threat to the quality of life for many Kentuckians and their families. Recent statistics indicate drug offenders account for a significant portion (in one year, 52,597 arrests were made for drug violations statewide) of individuals within thecriminal justice system, directly affecting the economic vitality within our state (Bunn & Slavova, 2012; Federal Bureau of Investigation, 2012). These statistics signify an overwhelming need for effective prevention efforts and innovative treatment alternatives. This study provides an innovative alternative treatment for drug offenders that infuses social and emotional coping strategies using percussion as a context. During the innovative program participants were able to express, recognize, articulate and evaluate themselves and their peers’ emotional coping strategies while developing peer camaraderie. They did so while being introduced to rudimentary drumming skills, fusing emotional intelligence with the art of drumming. The hypothesis is that this innovative program will enhance participant emotional intelligence to express, learn an effective coping skill, and establish camaraderie with their peers.
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Hemingway, Judith Frances Mary. "Spatializing drugs discourses : cultural geographies of illicit drug-using." Thesis, University College London (University of London), 2003. http://discovery.ucl.ac.uk/10020432/.
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Foulkes, Broderick M. "Developing novel drug delivery methods for anti-leishmanial drugs." Thesis, Griffith University, 2020. http://hdl.handle.net/10072/393974.
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Background: Leishmaniasis is a DNDi listed disease caused by protozoan parasites of the kinetoplastida class. The disease currently spans over 80 countries, across the New World and Old World, potentially affecting 500 million people with 1 million new cases reported annually. Leishmaniasis is a vector-driven disease, utilizing two genus of sand fly, Phlebotomus sand fly is responsible for Old World transmission, whereas the Lutzomyia sand fly is responsible for New World transmission. The two main stages of leishmaniasis, are the diagnostic stage (promastigote in sand fly) and the infective stage (amastigote in mammalian cells). Dependent on strain, geography and location of infection, there are three main forms of leishmaniasis: cutaneous (subdivided into diffuse-cutaneous leishmaniasis (DCL) and disseminated-cutaneous leishmaniasis (DL)); mucocutaneous; and visceral (subdivided into post-kala azar dermal leishmaniasis (PKDL)).
The DNDi status of leishmaniasis indicates that the pharmaceutical interest into research and development is shockingly low, resulting in very little progress into new treatments, limited to current therapeutics that suffer from severe toxicities (cardio, nephro, hepato, oto). These issues can be circumvented by utilising liposomal drug-carriers, as part of an increased interest in nanoparticle research across all glycosciences, modifying these drugs to interact better with the target cell or liposomal carrier can be of great benefit.
Aims and Objectives: This project investigated the modification of current therapeutics in leishmanial treatment, paromomycin and compare the changes in antimicrobial efficacy. These modifications would revolve around enhanced binding affinity for macrophages and for liposomal carriers. This was achieved by modifying paromomycin at its reactive primary alcohols, using previously explored chemistry to attach long-chain fatty acids (LCFAs) to these reactive groups to create potential prodrugs. These were then subject to comparative kill efficiency studies against S. aureus, P. aeruginosa, and L. donovani DD8 cells in MIC assays and a resazurin based assay. A further objective was to investigate novel drug targets in leishmania, using LCFA-ligase as a potential target, as it has been reported this protein is differentially expressed, showing prominence and a potential for inhibition. This compound was also tested against L. donovani DD8 in the resazurin based assay.
Methods: Paromomycin laurate and palmitate-based derivatives were synthesised by simple esterification, and the LCFA directive synthesised tert-butyl (4-(2-(decanesulfonyl)acetamido)butyl)carbamate) (N-Boc DSA) was synthesised by known methods. These compounds were characterised and subjected to MIC assays on S. aureus and P. aeruginosa, and a resazurin-based high content imaging (HCI) assay on axenic amastigotes of L. donovani DD8. Parallel synthesis and testing of neomycin LCFA derivatives were made by Dylan Farr, and tested against the same pathogens, comparatively with paromomycin derivatives.
All experiments were conducted in triplicate and quadruplicate, with statistical differences being analysed by two-way analysis of variance (Two-way ANOVA). Values with P<0.05 were considered significant.
Results and Discussion: Paromomycin palmitate and dipalmitate were synthesised with preference on dipalmitate testing due to increased binding affinity for liposomal carriers and macrophages. Laurate synthesis was much less effective under a multitude of conditions. Secondary compound Boc-DSA was synthesised for use in conjunction with the paromomycin derivatives. The paromomycin dipalmitate compound was tested against S. aureus and P. aeruginosa, with comparative aminoglycosides: neomycin palmitate, amikacin palmitate, and kanamycin palmitate. Against S. aureus, all compounds showed reduced activity at all concentrations, with paromomycin and amikacin being the least affected. Lower concentrations of antibiotic saw antagonistic effects with the lipid chain synergistically enhancing bacterial growth. P. aeruginosa testing was inconclusive due to increased pyocyanin expression, potentially increasing biofilm aggregation of the bacterial cells, reducing interactable surface-area for the aminoglycosides. Further testing with biofilm disruptors in conjunction may show improved results.
Candidates paromomycin dipalmitate, N-Boc DSA, and neomycin palmitate were tested by V.Avery group at GRIDD (Griffith Institute for Drug Discovery) against L. donovani DD8 axenic amastigotes. Results showed <50% activity among derivative candidates, with lower activity even for paromomycin, a known anti-leishmanial agent. Morphological and pathophysiological changes due to geographical variations in leishmanial strains have been reported to have different effects on therapeutic efficacy. Although the reduced activity of the candidates can be noted for the DD8 strain, further testing on a variety of geographically relevant strains may show different activities. Human monocyte cytotoxicity THP-1 assays were performed in conjunction, <50% activity was similarly found for the described compounds.
Conclusions and Future Remarks: Overall, the modification of ring-1 C6’ and ring-3 C5’ into a LCFA-derivative via esterification chemistry showed reduced activity at all concentrations against S. aureus, P. aeruginosa, and L. donovani DD8 amastigotes. Similar for comparative aminoglycosides of neomycin, amikacin, and kanamycin, although results against P. aeruginosa indicate potential biofilm aggregation. The reference compounds, including DSA, tested against L. donovani DD8 showed <50% inhibition, this may be indicative of morphological and pathophysiological changes due to geographical differences in the test strain. Future avenues worth pursuing is a range of LCFA-derivatives such as C10,12,14,18 for synergistic studies. The use of biofilm disruptors in conjunction with the reference compounds may improve P. aeruginosa activity, in addition to biofilm disruptors, the addition of surfactants to improve solubility of the LCFAs, these additions may have antagonistic effects and are worth investigating. Further testing among various geographically relevant strains of L. donovani would prove the theory put forth by Stuart et al. and show the efficacy of the reference compound across multiple geographically-dependent strains. Incorporation of the test compounds into liposomes were not achieved within this project, however investigations against the aforementioned L. donovani DD8 amastigotes, and against RAW 264.7 cells using the encapsulated compounds as comparative data is warranted.Thesis (Masters)
Master of Medical Research (MMedRes)
School of Medical Science
Griffith Health
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Pavuluri, Nina. "Development and evaluation of drug-admicelle systems for poorly soluble drugs : a novel surfactant templated drug delivery platform /." Full text available from ProQuest UM Digital Dissertations, 2008. http://0-proquest.umi.com.umiss.lib.olemiss.edu/pqdweb?index=0&did=1781035201&SrchMode=1&sid=1&Fmt=2&VInst=PROD&VType=PQD&RQT=309&VName=PQD&TS=1258661510&clientId=22256.
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Thesis (Ph.D.)--University of Mississippi, 2008.Typescript. Vita. Major advisor: John O' Haver "June 2008." Includes bibliographical references (leaves 120-163). Also available online via ProQuest to authorized users.
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Wong, Ka Yeung Mark. "Drug clearance mechanisms and chemotherapy response." Thesis, The University of Sydney, 2007. https://hdl.handle.net/2123/28094.
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Cytotoxic chemotherapeutic agents have a major role in the treatment of cancers. However, many cytotoxic agents have a narrow therapeutic window with best treatment response achieved only within a small range of drug concentrations.
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Chan, Kin-yi Ivy. "A study of determinants of relapse in psychotropic substance abuse /." Hong Kong : University of Hong Kong, 1995. http://sunzi.lib.hku.hk/hkuto/record.jsp?B19470757.
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Claborn, Jordan, Moses Holleyman, and John B. Bossaer. "Consistency of Drug Information Resources in Identifying Drug-drug interactions with Oral Antineoplastic Agents." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/2346.
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Targeted oral antineoplastic agents (OAs) have become a staple and rapidly growing field in the realm of cancer treatment. As with any chemotherapeutic/narrow spectrum agent, clinicians have to be aware of potential drug interactions that could interfere with therapy. Drug information databases are a common resource utilized to check for interactions between agents and patient's home medications. A major concern with OAs is that they are usually taken at home as well as picked up at a pharmacy by the patient themselves. With this kind of therapy adherence and patient side effect reporting becomes a concern. We wanted to determine the reliability of these databases for picking up potential interactions with patients on OAs. We accessed hospital records to find patients with various malignancies on OAs between the calendar year of 2013-2014, of which we found 876 that were screened for potential use of OAs. The goal was to find patients on OAs specifically and determine the number of drug interactions flagged by either drugs.com and/or Lexicomp®. In addition, the significance of the interaction as well as disagreements between databases were analyzed. A major interaction by Lexicomp® is defined as either a ‘D’ or an ‘X’ level interaction and on drugs.com is labeled ‘major.' Of the 876 screened we found 16 patients (one patient had tried 3 different agents, and another patient had tried two) on OAs. Lexicomp® flagged overall 42 interactions amongst all subjects, of which 17 were major interactions. Drugs.com flagged overall 44 interactions amongst all subjects, of which 11 were major interactions, being the more conservative of the two. Between the 2 databases there were 10 out of 18 major interactions that both were in agreement upon. These discrepancies are of concern in that clinicians hope that resources they utilize are incongruent with one another and allow them to practice in the safest manner in terms of avoided potential serious drug interactions whether it be harm to a patient or decreased effectiveness of the OA. Now that all patients have been screened, future research would be to determine the clinical significance of these interactions and whether or not they had an effect on patient outcomes.
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Clayborn, Jordan, Moses Holleyman, and John B. Bossaer. "Reliability of Drug Information Databases in Identifying Drug-drug Interactions with Oral Antineoplastic Agents." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etsu-works/2349.
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Wang, Yan. "Peptide-drug conjugate for Her2-targeted drug delivery." Scholarly Commons, 2018. https://scholarlycommons.pacific.edu/uop_etds/3567.
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Recent strategies for anticancer drug design have been focused on utilizing antibody as a drug or targeted moiety for targeted drug delivery. Antibody−drug conjugates (ADCs) have become a promising new class of targeted therapeutic agents for treatment of cancer. ADCs are designed to preferentially direct a cytotoxic drug to a cell-surface antigen recognized by an antibody. However, there are some challenges in developing ADCs, such as limited solid tumor penetration, high manufacturing costs and antibody-drug stoichiometry. Smaller molecules such as peptides have been shown to specifically bind to cancer related targets. These peptides can be used to form peptide-drug conjugates (PDCs) to overcome above-mentioned drawbacks presented by ADCs.
In this study, it was hypothesized that novel synthesized PDCs can be a strategy for breast cancer therapy. HER2 specific binding peptides, MARAKE and MARSGL, were modified by addition of a cysteine at C-terminus. The modified peptides were coupled with monomethylauristatin E (MMAE) by using maleimidocaproyl (MC) as a non-cleavable linker to form peptide-drug conjugates (YW1, YW2) and maleimidocaproyl-valine-citrulline (MC-VC) as a cleavable linker to form peptide-drug conjugates (YW3 and YW4). The peptides, peptide-drug conjugates and MC-MMAE, MC-VC-MMAE were characterized using ESI-MS and purified by using high-performance liquid chromatography (HPLC). Cellular uptake study was performed to determine binding specificity and internalization of two HER2 specific peptides and cysteine-modified peptides (MARAKEC, MARSGLC). In vitro cell viability assay was conducted to assess the cytotoxicity and determine the targeting specificity as well as the potency of the peptide-drug conjugates.
The purity of each compound was greater than 90%. Internalization of both HER2 specific binding peptides and cysteine-modified peptides were significantly higher than random peptides in HER2 over-expressed cell lines, MDA-MB361 and ZR75, while negligible uptake in HER2 negative cell line, HEK293. MC linked PDCs showed similar cytotoxicity as peptide in all cell lines; while MC-VC linked PDCs have higher cytotoxicity than MMAE in HER2 positive cell line and significant lower cytotoxicity than MMAE in normal cell line HEK293. However, PDCs with MC link do not show significant difference in cytotoxicity compared to the peptide in all cell lines.
In conclusion, specificity of HER2 binding for both peptides was preserved after modification with cysteine. The derivation of MMAE to link drug and peptide played a crucial role in the anticancer activity. Peptide-MMAE conjugates with cleavable linker showed a promising targeting capability for delivery of MMAE to HER2 overexpressed cancer cells.
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Herzberg, Benjamin. "Fluorous Drug-Affinity Proteomics for Cancer Drug Discovery." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:15821582.
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Identifying the intracellular targets of small molecules – target ID – is a major problem in chemical biology with broad application to the discovery and development of novel therapies. Traditional target ID studies have relied on drug-affinity chromatography to separate biological mixtures combined with mass spectrometry shotgun sequencing for peptide identification. This workflow is limited, however, by low specificity for unique peptides, high demand for cellular material, unknown depth of profiling, and other problems. To address these problems, we explore and describe here a novel strategy for cell lysis and drug-affinity that we call “fluorous proteomics.” By conjugating a small molecule to a perfluorinated alkane, we hypothesized that we could achieve superior recovery, specificity, and identification, allowing us to identify previously unknown drug targets with drug-affinity methods. We establish the conditions for fluorous proteomics and synthesize fluorinated probes for two drugs as a proof-of-concept. Lenalidomide, a derivative of thalidomide with unknown intracellular targets but widespread clinical use, is investigated and novel binders are identified. A particular derivative, 5HPP33, is singled out for potential future drug development. JQ1, an inhibitor of BET bromodomains in development as a treatment for hematological malignancies, is used to compare biotinylated versus fluorous tags and to identify new binders of possible therapeutic relevance. We conclude that fluorous proteomics retains high potential as an alternative to traditional drug-affinity chromatography strategies and may aid in target ID going forward, but is not without complications.
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Hartmann, Neil Godfried. "Intercalative drugs in cancer chemotherapy : two approaches towards drug development." Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292983.
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Kaza, Lakshmi S. "Novel Thermal Analytical Techniques to Characterize Drugs and Drug Delivery." Cleveland State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=csu1317258017.
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Kigen, Gabriel Kimutai. "Assessment of Drug Interactions Between Antiretroviral and the Anthelminthic drugs." Thesis, University of Liverpool, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.507508.
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Vaidya, B. K. "Chiral separation of drugs and drug intermediates by immobilized biocatalyst." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2009. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/2773.
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Zhang, Huarui. "Design, synthesis and activity evaluation of novel exosome inhibitors." HKBU Institutional Repository, 2020. https://repository.hkbu.edu.hk/etd_oa/849.
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Background: Exosomes are extracellular vesicles (EVs) that produced in the endosomal compartment of most eukaryotic cells, and have observed increasing attentions over the past decades. They play important roles in cell- to-cell communications, they can carry varieties of substances, like proteins, nucleic acids and lipids, to the target cells they encounter. These cargos could influence the function of recipient cells. This novel mode of intercellular communication is found to be of critical importance to many cellular activities. However, exosomes are involved in various diseases processes. Tumor- derived exosomes could promote cancer progression, and our preliminary study indicated that exosome released from osteoclasts could inhibit bone formation. We also found that osteoarthritis (OA) progression in OA mice could be attenuated by inhibiting exosomes released by osteoclasts. Therefore, inhibition of exosome release has potential value in the treatment of diseases. The exosome release is under control by RAB27A, which is a protein involved in protein transport and signal transduction. It is reported that a compound named Nexinhib20 could selectively inhibit RAB27A, but this compound is highly toxic to RAW264.7 cells, which IC 50 is 1.5 µM. Therefore, for safety concerns, it has to be chemically modified to reduce toxicity. Aim: (1) To design and synthesize a series compounds based on the structure of Nexinhib20. (2) To evaluate the toxicity and exosome inhibiting activity of the synthesized compounds and discuss the structure-activity relationships (SAR) of them. Materials and Methods: Nexinhib20 derivatives were synthesized by aldol reaction. The cytotoxicity of these compounds was evaluated by MTT assay. The exosome inhibiting activity of these compounds was evaluated through exosome isolation and quantitation. Result: A series of compounds were synthesized and their structures were confirmed by LC-MS and NMR. The structure-activity relationships of these compounds were discussed, and the results showed that compounds A3, A23 and B2 exhibited lower toxicity compared to Nexinhib20 and strong exosome inhibiting ability. Conclusion: The results of this project indicate that A3, A23 and B2 exhibited low toxicity and good exosome inhibiting activity. Based on this, further chemical modification could be applied to develop new exosome inhibitors with better efficacy
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Nissen, Lisa Monique. "Quality use of medicines : from drug use evaluation to rural community pharmacy practice /." St. Lucia, Qld, 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16549.pdf.
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Tayob, Shamima. "Challenges in the management of drug supply in public health centres in the Sedibeng District, Gauteng Province." Thesis, University of Limpopo (Medunsa Campus), 2012. http://hdl.handle.net/10386/683.
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Thesis (MSc(Med)(Pharmacy))--University of Limpopo, 2012.ABSTRACT South Africa, 80% of the population is dependent on the vernment to provide for their health care needs, mainly ugh primary health care facilities. In the health objectives of the National Drug Policy, the government of South Africa outlines its commitment to ensuring availability and accessibility of medicines which are effective, affordable, safe and of good quality in all sectors of the health care system ( N a t ion a IDe par t men t of He a It h, 1 996) . In o rd e r to assess the availability of d ru g s and identify ch a II en g e s w hi c h . ex is tin the Emf u Ie n i sub - d is t r i c t wi t hi nth e Sedibeng district, a questionnaire was administered to 21 primary health care facility managers/store managers, fo u r Community Health Centre managers and five transport officers in the district. In addition, a document review process was conducted to verify aspects of th e facility managers' and store managers' responses. Bin cards and primary health care order files were also examined in conjunction with a checklist to establish whether stock control systems were in place. There was a 100% response with all primary health care centres and community health care centres completing th e questionnaires. It was established that drugs at primary and community health care clinics were procured from the Sedibeng district pharmacy. In each of these clin ics there were specific individuals responsible for medicine supply management. Only four primary health care clinics had full-time pharmacist assistants employed, and 14 clinics were visited by the assistants on a weekly/bi-weekly basis. There were no employees that have received training in drug supply management in the last 12 months in 88% of the clinics interviewed. Nineteen clinics claimed that the storage area was not large e n 0 ugh to s tor e a II the s toe k f or a m 0 nth's sup ply and 0 n I yon e clinic had a secure delivery area for their medication. It was established that 24 facilities received stock by two specific procedures namely; that the number of boxes were checked and the driver's note was then signed, and stock received was checked against the invoice. Of the interviewed cl i nics, 20% admitted that the re-order level had not been calculated for all tracer items in the store. Standard Operating Procedures, Standard Treatment Guidelines and the Essential Drugs List were also not available at all facilities. The results indicate inadequacies and weaknesses in procurement, quantification, stock control, storage and record keeping. It clearly demonstrates that inadequately-trained staff was a ma j 0 reo n t rib uti n g fa c tor to d rug s h 0 r tag e s. The r e was a I a c k 0 f monitoring and evaluation by th e district pharmacy as pharmacists did not manage to visit all the clinics each month. Most of the inadequacies and weaknesses can be addressed at facility level with pro per supervision, in-service training, mentoring and support of staff and the reinforcement of drug supply management training. Regular supervisory visits together with updating the monitoring too I in terms of th e problems identified will improve th e management of drugs and ultimately decrease the number of out of stocks where problems have been identified at primary health care level.
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Kwan, Ming-tak Kalwan, and 關明德. "Drug careers: an interactional pathway into adolescent drug-use." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29757678.
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Suhardi, Vincentius Jeremy. "Drug eluting prosthetic joints through drug cluster morphology control." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/111323.
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Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 299-330).
More than one million joint replacements are performed in the USA annually. However, around 10 % of patients require revision surgery within 10 years with prosthetic joint infections (PJI) as a common reason. PJI has a recurrence rate of 16 %, a mortality rate of 2.5 %, and end-stage treatments involving arthrodesis and amputation. Most drug eluting polymers that were in development to address this problem failed due to toxic degradation products, insufficient drug release, and insufficient mechanical strength. The gold standard of treatment uses antibiotic eluting bone cement which has a mechanical failure rate of 26-60 % within 49-54 months if used under load bearing conditions. Therefore, despite advances in orthopedic materials, development of drug-eluting devices with effective, sustained delivery with the necessary mechanical strength for a fully load bearing joint implant has been elusive. Here, we report the synthesis and application of a drug eluting, fully load bearing, and articulating joint prosthesis that has superior mechanical strength and drug elution profile compared to the clinical gold standard, antibiotic eluting bone cement. We modified the eccentricity of drug clusters and percolation threshold in the polymeric matrix of Ultra-High Molecular Weight Polyethylene (UHMWPE), which resulted in maximized drug elution and mechanical strength retention. The optimized antibiotic eluting UHMWPE elutes antibiotic at a higher concentration for a longer period of time than antibiotic eluting bone cement while retaining the mechanical and wear properties of clinically used UHMWPE joint prosthesis. After drug elution, the empty drug clusters in the polymer were filled with biological lubricants during articulation, which through a combination of weeping and elastohydrodynamic lubrication, reduced the overall wear rate of the UHMWPE. Treatment of Staphylococcus aureus infected lapine knee with the antibiotic eluting UHMWPE showed complete bacterial eradication without any detectable systemic side effect. Taken together, our study showed that the drug-eluting UHMWPE joint implants in this study are promising candidates for further clinical trial and as the next generation prosthetic joints.
by Vincentius Jeremy Suhardi.
Ph. D. in Medical Engineering and Medical Physics
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Clark, Justin. "An evaluation of Warfarin and Statin Drug-Drug Interactions." The University of Arizona, 2012. http://hdl.handle.net/10150/623593.
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Class of 2012 AbstractObjectives: To evaluate the literature with respect to drug-drug interactions of the hydroxymethylglutaryl CoA reductase inhibitors atorvastatin, fluvastatin, lovastatin, pitavastitin, pravastatin, simvastatin, and rosuvastatin with warfarin. Methods: This descriptive retrospective study identified articles reporting on each drug-drug interaction from the online databases PubMed (1970 – February 2012) and the drug compendia Micromedex and Facts & Comparisons. The studies included in this investigation were primary literature reports, written in English with human subjects. All studies included were evaluated using the van Roon 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions. This scale rates the study type from lowest to highest quality, from zero to four. Case-reports were evaluated using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction. Results: Twenty studies met the inclusion criteria. One study involved atorvastatin, four for fluvastatin, three for lovastatin, 2 for pitavastatin, 1 for pravastatin, 5 for rosuvastatin, and 6 for simvastatin. The mean van Roon quality of evidence score was 2.1+/- 0.74, the mean score for atorvastatin, pitavastatin, and pravastatin was 3, with the mean score of fluvastatin, lovastatin, rosuvastatin, and simvastatin was 2. 70% of the literature reviewed were case-reports or letters. Conclusions: The studies and reports supporting HMG-CoA reductase inhibitors and warfarin drug-drug interactions are most commonly case- reports and are of low quality and quantity.
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Clark, Justin, and Daniel Malone. "An Evaluation of Warfarin and Statin Drug-Drug Interactions." The University of Arizona, 2012. http://hdl.handle.net/10150/614476.
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Class of 2012 AbstractObjectives: To evaluate the literature with respect to drug-drug interactions of the hydroxymethylglutaryl CoA reductase inhibitors atorvastatin, fluvastatin, lovastatin, pitavastitin, pravastatin, simvastatin, and rosuvastatin with warfarin. Methods: This descriptive retrospective study identified articles reporting on each drug-drug interaction from the online databases PubMed (1970 – February 2012) and the drug compendia Micromedex and Facts & Comparisons. The studies included in this investigation were primary literature reports, written in English with human subjects. All studies included were evaluated using the van Roon 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions. This scale rates the study type from lowest to highest quality, from zero to four. Case-reports were evaluated using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction. Results: Twenty studies met the inclusion criteria. One study involved atorvastatin, four for fluvastatin, three for lovastatin, 2 for pitavastatin, 1 for pravastatin, 5 for rosuvastatin, and 6 for simvastatin. The mean van Roon quality of evidence score was 2.1+/- 0.74, the mean score for atorvastatin, pitavastatin, and pravastatin was 3, with the mean score of fluvastatin, lovastatin, rosuvastatin, and simvastatin was 2. 70% of the literature reviewed were case-reports or letters. Conclusions: The studies and reports supporting HMG-CoA reductase inhibitors and warfarin drug-drug interactions are most commonly case-reports and are of low quality and quantity.
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Larson, Joeanna Lee. "Perinatal Drug Abuse Intervention: Policy Development for Drug Screening." ScholarWorks, 2016. https://scholarworks.waldenu.edu/dissertations/2555.
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Perinatal drug abuse is becoming a profound issue facing the health and wellbeing of neonates. The community serviced by the project site, which lies within the boundaries of an Indian Reservation, suffers from perinatal drug abuse at a higher rate than state and federal averages. The purpose of this project was to provide the project site with a policy to consistently screen for perinatal drug abuse. Lave's theory of situational learning and the Sanford Way model for quality improvement framed this project. To guide policy development, data were compiled through a systematic review of current literature, national and state guidelines, state law, local tribal government, and community stakeholders. Data included: (a) studies completed in the past 10 years specifically targeting drug abuse in child-bearing aged women, with intentional exclusion of tobacco and alcohol studies; (b) prevalence of illicit drug abuse in child bearing aged women at a local, state, and national levels; and (c) local, state, and national guidelines, as well as state law, for perinatal drug abuse intervention and screening. In addition, interviews and meetings with local stakeholders were completed and their feedback was incorporated into the development of the perinatal drug abuse screening and intervention policy. To evaluate policy effectiveness, it is proposed that perinatal drug screens ordered at the project site be monitored for six months prior to and after implementation of the new policy. The desired outcome will be that providers consistently intervene with perinatal drug abuse in a non-biased fashion. This quality improvement project will create a positive social change by allowing non-biased intervention with perinatal drug abuse using evidence-based practice and by promoting nursing-driven policy development.
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Wheeler, Daniel Wren. "Weakened by strengths : drugs in solution, medication error and drug safety." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:238087a5-120b-4a3d-9437-5840cecf8b6a.
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The concentrations of some drug solutions are often expressed as ratios or percentages. This system simplified prescription and dispensing when Imperial measures such as grains and minims were used. Ampoules of powerful vasoactive drugs such as catecholamines and potentially toxic local anaesthetics are still labelled as ratios and percentages, seemingly through habit or tradition than for any useful clinical reason. This thesis argues that adherence to this outdated system is confusing, causes drug administration errors, and puts patients at risk. Internet-based questionnaires were used to quantify medical students’ and doctors’ understanding of ratios and percentages. A substantial minority of almost 3000 doctors could not convert between ratios, percentages and mass concentration correctly, made dosing errors of up to three orders of magnitude in written clinical scenarios, and struggled with conversions between metric units. These findings are strong arguments for expressing drug concentrations as mass concentration and providing better drug administration teaching. High fidelity patient simulation was used to examine the influence of clearer ampoule labelling and intensive drug administration teaching. This allowed critical incidents to be reproduced realistically, clinical performances to be assessed, and outcome measures to be accurately recorded. Randomised controlled trials were conducted that demonstrated positive influences of both interventions for doctors and students. The difficulties that nurses encounter when preparing infusions of these drugs on critical care units were also studied and are reported. The findings presented should be sufficient to persuade regulatory authorities to remove ratios and percentages from ampoule labels – a straightforward, cheap, commonsense intervention. The lack of effective clinical error reporting systems and the extreme practical difficulties of conducting clinical trials in this field mean that a firm link between this intervention and patient outcome is unlikely ever to be made, but this should not be an excuse for maintaining the status quo.
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Parker, S. M., and John B. Bossaer. "Comparison of Drug Information Resources in Identifying Drug-drug Interactions in Newly Approved Oral Antienplastic Agents." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etsu-works/2343.
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Michaelsen, Maria Høtoft. "The effect of digestion and drug load on absorption of poorly water soluble drugs from self-nanoemulsifying drug delivery systems (SNEDDS)." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/59178.
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Patel, Fadheela. "Development of a cost-effective drug sensitivity test for multi-drug resistant and extensively drug-resistant tuberculosis." Thesis, Cape Peninsula University of Technology, 2010. http://hdl.handle.net/20.500.11838/1496.
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Thesis (MTech (Biomedical Technology))--Cape Peninsula University of Technology, 2010The World Health Organisation estimates that nine million people are infected with tuberculosis (TB) every year of which ninety-five percent live in developing countries. Africa has one of the highest incidences of TB in the world. but few of its countries are equipped to diagnose drug-resistant TB. This study aimed to develop a robust. yet simple and cost-effective assay. which would require minimal sophisticated instrumentation and specialised personnel that would make drug sensitivity screening for multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) accessible to resource-poor high-burden settings. A four-quadrant colorimetric agar plate method was developed which showed good specificity (97.3%-100%) and sensitivity (77.8%-100%) compared to the polymerase chain reaction (PCR) method used as gold standard. Agreement between the methods. using Simple Kappa Coefficients. ranged between very good and excellent. all with high statistical significance (P < 0.0001). The currently used BACTEC MGIT SIREN sensitivity assay coupled with the E-test® strip method. as routinely used in the TB reference laboratory. was compared and showed excellent comparison with the newlydeveloped plate method. for each antibiotic tested. as well as the resultant monoresistant, MDR- or XDR-TB diagnoses. Moreover. the new method was found to be extremely cost-effective. priced at half the cost of a peR assay. These four quadrant plates. with a colorimetric indicator and selected antibiotics. can be considered as an economic altemative or a complimentary method for laboratories wishing to reduce the cost and complexity for TB drug sensitivity testing. Routine diagnostic testing would thus be made more accessible and affordable to laboratories that are not presently diagnosing drug resistant TB. therefore enhancing case detection and treatment in the resource-poor settings hardest hit by this curable disease.
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Pan, Xiaolei. "THE SLC22 TRANSPORTER FAMILY: NOVEL INSIGHTS TO ROLES IN DRUG EFFICACY, DRUG-DRUG INTERACTIONS AND MOOD DISORDERS." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3983.
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Numerous studies have demonstrated the impact of organic cation (OCTs; SLC22 family) and anion transporters (OATs; SLC22 family) on the efficacy and safety of clinically important therapeutics. To be specific, OCTs and OATs have been identified as determinants for uptake into and secretion from enterocytes, hepatocytes and renal proximal tubular cells, and are frequent sites of drug-drug interaction (DDI). In addition, OCTs expressed in brain are components of the low-affinity, high capacity clearance pathway (uptake-2) for biogenic monoamine neurotransmitters. As a result, OCTs may represent novel targets for mood disorders.
The inhibitory effects of several therapeutic agents, designed drugs and novel compounds were assessed on the function of OCTs/Octs and OATs/Oats. Among these compounds, the anthraquinone rhein showed significant inhibition on hOATs. While the antituberculosis drug ethambutol, the herbal products matrine and oxymatrine, synthetic cathinones, and all quinazoline and guanidine compounds produced significant inhibition on hOCT activity with most IC50 values in the micro- and even nanomolar ranges.
Considering the clinically relevant unbound concentrations in biofluids, significant DDI potentials were found for rhein, ethambutol, matrine, oxymatrine and several synthetic cathinones affecting enterocytes, hepatocytes and/or proximal tubules. As hOCT2 and hOCT3 may participate in modulating neurotransmitter homeostasis in the CNS, these findings also suggested that the CNS pharmacological effects of synthetic cathinones, quinazoline and guanidine compounds might be due to their inhibitory effects on OCTs; although their impact may be limited solely to clearance of these compounds. Based upon their in vitro OCT/Oct inhibition profiles, three lead quinazoline and guanidine compounds were chosen for in vivo studies. Potent antidepressant-like effects of one lead hOCT-interacting compound (KEO-099) were re-confirmed in the tail suspension test. While in vivo results of the two newly identified hOCT-interacting lead compounds were somewhat less clear.
Finally, homology modeling and docking studies for hOCT3 identified key amino acid residues that might be involved in interaction between hOCT3 and small molecules. Subsequent experiments confirmed a competitive mode of interaction between MPP+ and lead compounds on hOCT3. Thus, preliminary analysis indicates our hOCT3 homology model can be used to support rational drug design and high-throughput screening of novel hOCT substrates/inhibitors.
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Unell, Ira. "Problem drug users and drug workers : their beliefs in the origins and treatment of problem drug use." Thesis, Loughborough University, 1997. https://dspace.lboro.ac.uk/2134/6843.
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Lickteig, Andrew Joseph. "Drug Metabolizing Enzyme, Drug Transporter Expression And Drug Disposition Are Altered In Models Of Inflammatory Liver Disease." Diss., The University of Arizona, 2007. http://hdl.handle.net/10150/193836.
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Correct dosing in pharmacotherapeutics is based on the idea that too much of a drug will cause toxicity, while too little will result in failure to elicit the desired response. A major factor in the ability of a patient to handle any dose of a drug is the capacity to metabolize and eliminate that drug from the body. For the vast majority of drugs, the liver plays a key role in determining the rate at which drugs are eliminated. First, drugs must be taken up across the cell membrane into hepatocytes by uptake transporters. Once inside the hepatocyte, biotransformation enzymes metabolize and conjugate the drug to a more water-soluble compound, the distribution of which is more easily controlled. These water-soluble metabolites are then transported out of the hepatocyte by additional drug transporters either into bile for elimination, or back into the blood.More than 2 million severe adverse drug reactions occur in the US each year and often result from interindividual variation in the ability to metabolize and eliminate drugs. This number does not include medical errors, but rather circumstances where an individual is unable to handle the standard dose of the correctly prescribed drug. Although genetics plays an important role, the greatest source of variation comes from other environmental factors such as disease states. Nonalcoholic fatty liver disease (NAFLD) is a chronic condition that comprises a spectrum of histopathologies that range from simple steatosis to the more severe steatohepatitis. Specifically, nonalcoholic steatohepatitis (NASH) has become one of the leading causes for liver transplantation in the United States, and thus clearly become a considerable burden to the U.S. healthcare system.It is not known whether the capacity of the liver to metabolize and excrete drugs is altered in patients with NASH. Because the liver plays such a critical role in drug metabolism and disposition, any disease state that disrupts or modifies these functions will alter the fate of a given drug within the body. It is therefore very likely that the ability of the liver to metabolize and excrete clinically relevant drugs is compromised in NASH patients.
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Mahaguna, Vorapann. "Investigation of cellulose ether polymers in controlled drug delivery." Access restricted to users with UT Austin EID Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3037524.
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Tooley, Jennifer. "Demon drugs and holy wars, Canadian drug policy as symbolic action." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ54654.pdf.
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Banks, Simon. "Incompatibilities between HPMC and model drugs : consequences for extended drug release." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421473.
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Javaheri, Hoda. "Wet granulated liquisolid drug delivery systems with hydrophobic and hydrophilic drugs." Thesis, University of Sunderland, 2017. http://sure.sunderland.ac.uk/8549/.
Full textAbstract:
The formulation of hydrophobic drugs into appropriate dosage forms is challenging due to the problems associated with those drugs such as low solubility and poor dissolution. Using a liquisolid system is a promising method to improve the dissolution of hydrophobic drugs and in sustaining the release of hydrophilic drugs, in which solid drugs are dispersed in non-volatile liquid vehicles. The aim of this research was to use the liquisolid technique to enhance the dissolution rate of glibenclamide, a model hydrophobic drug, and to sustain the release of metformin-HCl, as a model hydrophilic drug. The wet granulation process was applied to liquisolid powders with the aim of overcoming issues of poor powder flowability and compressibility, especially using high viscosity liquid vehicles. This process was performed with liquisolid powders prior to compaction into tablets. Different liquisolid formulations were prepared using three liquid vehicles (polyethylene glycol400 (PEG® 400), Synperonic® PE/L44 and Cremophor® ELP), at 10 and 30 % w/w drug concentrations for glibenclamide; and 30% and 60% w/w drug concentrations for metformin-HCl. Avicel®PH102 was used as a carrier, whilst colloidal silicon dioxide was employed as a coating material to convert the wet mixtures into dry powders. Potato starch, 5% w/w, as a disintegrant was blended with the mixtures manually for 10 minutes and then 0.75% of magnesium stearate as a lubricant was added and mixed for 5 minutes. The final powder (depending on its flowability and compactability) was then compacted automatically using a single-punch tableting machine to give tablets with 4 mg for glibenclamide and 40 mg for metformin-HCl. Prepared liquisolid compacts were characterized by using British Pharmacopeia quality control tests: uniformity of weight, friability, disintegration, hardness and drug dissolution. iii It was found, for both drugs, that by application of wet granulation to liquisolid powder admixtures, the large-scale production of liquisolid compacts is feasible, which can be easily adapted to the pharmaceutical industry. In addition to enhancing the flowability and compressibility of the powders, the glibenclamide dissolution was also improved due to the enhanced binding of particles and because of the wetting effect of liquid vehicles on the hydrophobic drug, which make the drug more available for dissolution. For the sustained release preparations of liquisolid metformin-HCl, hydroxyl propyl cellulose (HPC) was used as a novel carrier in liquisolid compacts. The results showed 92% drug release after 12 hours using Cremophor®ELP (with 30% w/w drug concentration) which was the best sustained drug release formulation. Additionally, Eudragit® RL30D and Eudragit® RLPO have been used to study their effects on drug release from liquisolid formulations, examining if they can sustain or give more rapid drug release. Both types of Eudragit revealed immediate release with metformin-HCl rather than sustained drug release, with the tablets disintegrating within seconds. This suggests formulating orodispersible metformin-HCl tablets using Eudragit® RL30D as a liquid vehicle. In summary, liquisolid technology has led to promising results, not only in enhancing the drug dissolution of hydrophobic drugs, but also in sustaining and promoting the release of hydrophilic drugs.
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Wang, Shining. "DRUG DEVELOPMENT OF TARGETED ANTICANCER DRUGS BASED ON PK/PD INVESTIGATIONS." Diss., Temple University Libraries, 2008. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/2535.
Full textAbstract:
PharmaceuticsPh.D.
EGFR inhibitors, such as gefitinib, are examples of targeted anticancer drugs whose drug sensitivity is related to gene mutations that adds a pharmacogenetic [PG] dimension to any pharmacokinetic [PK] and pharmacodynamic [PD] analysis. The goal of this project was to characterize the PK/PD properties of gefitinib in tumors and then apply these results to design rational drug design regimens, and provide a foundation for future studies with EGFR inhibitors. Progressions of in vitro and in vivo studies were completed to understand the PK and PD behavior of gefitinib. In vitro cytotoxicity assays were first conducted to confirm the gefitinib sensitivity differences in a pair of human glioblastoma cell lines, LN229-wild-type EGFR and LN229-EGFRvIII mutant, an EGFR inhibitor-sensitizing mutation. Subsequent in vitro PD studies identified phosphorylated-ERK1/2 (pERK) as a common PD marker for both cell lines. To describe the most salient features of drug disposition and dynamics in the tumor, groups of mice bearing either subcutaneous LN229-wild-type EGFR or LN229-EGFRvIII mutant tumors were administered gefitinib at doses of 10 mg/kg intravenously (IV), 50 mg/kg intraarterially (IA) and 150 mg/kg orally (PO). In each group, gefitinib plasma and tumor concentrations were quantitated, as were tumoral pERK. Hybrid physiologically-based PK/PD models were developed for each tumor type, which consisted of a forcing function describing the plasma drug concentration-profile, a tumor compartment depicting drug disposition in the tumor, and a mechanistic target-response PD model characterizing pERK in the tumor. Gefitinib showed analogous PK properties in each tumor type, yet different PD characteristics consistent with the EGFR status of the tumors. Using the PK/PD model for each tumor type, simulations were done to define multiple-dose regimens for gefitinib that yielded equivalent PD profiles of pERK in each tumor type. Based on the designed PK/PD equivalent dosing regimens for each tumor type, gefitinib 150 mg/kg PO qd × 15 days and 65 mg/kg PO qd × 15 days multiple-dose studies were conducted in wild-type EGFR and EGFRvIII mutant tumor groups, respectively. In each tumor group, gefitinib plasma and tumor concentrations were measured on both day 1 and day 15, as were tumoral amounts of pERK. Different from single-dose model simulations, gefitinib showed nonlinear PK property in the wild-type tumor due to the down-regulation of membrane transporter ABCG2. Moreover, acquired resistance of tumoral pERK inhibition was observed in both tumor types. Nevertheless, gefitinib had an analogous growth suppression action in both tumor groups, supporting the equivalent PD dosing strategy. Overall, single-dose gefitinib PK/PD investigations in a pair of genetically distinct glioblastomas facilitated the development of hybrid physiologically-based PK/PD models for each tumor type, and further introduced a novel concept of PK/PD equivalent dosing regimens which could be applied in novel drug development paradigms. Preliminary multiple-dose gefitinib studies revealed more complex PK/PD characteristics that needed to be further explored.
Temple University--Theses
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MIELE, DALILA. "NANOPARTICLES AND NANOFIBERS AS DRUG DELIVERY SYSTEMS OF POORLY SOLUBLE DRUGS." Doctoral thesis, Università degli studi di Pavia, 2020. http://hdl.handle.net/11571/1321848.
Full textAbstract:
La via sistemica rappresenta la scelta più comune per la somministrazione di attivi e per lottenimento delleffetto terapeutico. Ad essa sono associate una serie di limitazioni tra cui la distribuzione aspecifica del farmaco responsabile della scarsa efficacia terapeutica e degli effetti collaterali che si tramutano in effetti tossici su siti differenti dal bersaglio terapeutico. Per questo motivo, vie di somministrazione a rilascio locale hanno di recente attratto la ricerca scientifica nel formulare sistemi in grado di veicolare lagente terapeutico su cellule o tessuti specifici; tale operazione è nota come drug targeting. In questo contesto, trovano largo interessa la nanomedicina e lingegneria tissutale, campi che in maniera sinergistica collaborano nellideazione di sistemi innovativi volti alla somministrazione del farmaco in situ. La strategia si basa sulla realizzazione di impianti intelligenti, capaci di risolvere limitazioni legate ai convenzionali sistemi di somministrazione. Numerose ricerche hanno messo in evidenza come sistemi nanoparticellari e sistemi nanofibrosi, ottenuti tramite limpiego di biopolimeri naturali e semisintetici, siano particolarmente efficaci nella veicolazione di principi attivi poco solubili o scarsamente biodisponibili. Quando opportunamente funzionalizzati e somministrati in prossimità del sito bersaglio, entrambi i sistemi favoriscono il rilascio sito-specifico del farmaco, riducendo lesposizione sistemica dellattivo, minimizzando la tossicità e migliorandone lefficacia. Lefficienza di tali sistemi è sia legata alla scelta dei biomateriali, ma soprattutto allelevata area superficiale data dalle dimensioni nanometriche. Biocompatibilità, biodegradabilità e capacità di essere facilmente suscettibili a modifiche chimiche sono aspetti ricercati nella formulazione di sistemi di rilascio di questo tipo. Il presente progetto di dottorato si inserisce in questo ambito ed è, specificatamente volto allottenimento di nanosistemi (nanoparticelle, nanofibre e/o sistemi ibridi) in grado di migliorare la biostabilità e la biodisponibilità di farmaci poco solubili e garantire un rilascio sito-specificoThe systemic route is the most common choice to administrate active molecules and to reach the therapeutic effect. Several limitations, including non-specific drug distribution, uncontrolled side effects and poor therapeutic efficacy that turn into toxic effects on sites different from the therapeutic target, mostly affect this route. For this reason, locally-released administration routes have recently attracted scientific research and novel systems aimed to carry therapeutic agents directly to specific cells or tissues are nowadays developed. In this context, nanomedicine and tissue engineering are broadly involved. These fields can work together in designing innovative and smart systems for in situ drug administration, solving all limitations linked to conventional drug delivery systems. Numerous studies have shown that nanoparticle and nanofibrous systems, obtained from natural and semi-synthetic biopolymers, are particularly effective in conveying poorly soluble or poorly bioavailable active ingredients. When properly functionalized or administered near the target site, both systems favor site-specific drug release, reducing systemic drug exposure, minimizing toxicity and improving its efficacy. The efficiency of these systems is linked either to the biomaterials employed, but especially to the high surface area given by the nanometric dimensions. Biocompatibility, biodegradability, and ability to be easily chemically modified are sought aspects during the formulation of this kind of nanosystems. This doctoral project is specifically aimed at developing novel polymeric nano-systems (nanoparticles, nanofibres and / or hybrid systems) able to improve biostability and bioavailability of poorly soluble drugs and guaranteeing a site-specific release.