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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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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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Hernández, Yulán. "Drugs". Revista de Química, 2016. http://repositorio.pucp.edu.pe/index/handle/123456789/101299.
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Dossou-Yovo, Flore. "Modification de la biodisponibilité orale des médicaments : interactions « Herb-Drugs » « Drugs- Drugs»". Thesis, Paris, CNAM, 2014. http://www.theses.fr/2014CNAM0936/document.
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L’administration par voie orale des médicaments reste encore de nos jours la voie royale de la prise des médicaments car moins onéreuse et plus adaptée au confort du patient. Mais cette voie reste toujours inaccessible pour certains médicaments comme les médicaments biologiques et les bio similaires voir certains anticancéreux et antirétroviraux.Le but de ce travail est d’améliorer la biodisponibilité par voie orale des médicaments à faible biodisponibilité par la mise au point d’un promoteur d’absorption. Pour y arriver nous avons adopté comme stratégie de développer un promoteur qui agit à la fois sur le passage passif et sur le passage actif des médicaments. Les études in vitro ont été réalisées en chambre de perméation d’Ussing adaptées par la société Biomécatronics SAS (BéthuneFrance). Dans la première partie de ce travail (Brevet), nous avons montré que l’utilisation d’une composition pharmaceutique et/ou diététique comprenant un extrait de plante(Hibiscus sabdariffa) pouvait augmenter la biodisponibilité in vitro des médicaments et des xénobiotiques qui passent par la voie paracellulaire comme le cisplatine (21 fois),l’oxaliplatine (11fois), la fluorescéine isothiocyanate-Dextran 4000 (3 fois), mais également les médicaments connus pour leur transport actif par la voie transcellulaire comme l’Efavirenz (7 fois) et l’Atazanavir (4 fois). Dans la seconde partie de ce travail, nous avons cherché à vérifier si notre promoteur d’absorption des médicaments a un effet sur la couche de mucus intestinale.Cette couche peut être un facteur limitant de passage des médicaments au travers de la barrière intestinale.Dans un premier temps (article 1), nous avons induit l’augmentation de la couche mucus au niveau du colon de rat après un prétraitement pendant une semaine avec le métronidazole. Puis nous avions confirmé (article 2) que l’administration par voie orale de deux antibiotiques le Cotrimoxazole (CTX) et le métronidazole (MTZ) pendant une semaine augmente la couche de mucus au niveau du côlon ; aussi nous avons montré qu’il existe une relation entre l’augmentation de la couche de mucus et la diminution de la conductance qui est l’index de transport passif des ions, des électrolytes et de certaines molécules à faibles poids moléculaires.De plus l’augmentation de la couche de mucus au niveau de l’intestin est responsable de la diminution du passage transépithélial des deux antirétroviraux dont l’utilisation est recommandée en première ligne par l’OMS (le.Ritonavir et l’Atazanavir) surles sujets porteurs du VIH (virus de l’immunodéficience humain). Après les traitements auMTZ et au CTX la sécrétion de l’Atazanavir augmente respectivement dans le côlon proximal de 2 et 4 fois et dans le côlon distal de 3 et 5 fois. On obtient également une sécrétion du Ritonavir de 5 et 10 fois dans le proximal et de 2 et 5 fois plus dans le distal.Le travail se poursuit par l’étude de l’effet de notre promoteur d’absorption des médicaments sur la couche de mucus intestinal.En conclusion, ce travail montre que l’on peut augmenter la biodisponibilité in vitroen utilisant les promoteurs de l’absorption des xénobiotiques qui agissent à la fois au niveau du transport passif et actifOral dosing is still seen as the silver bullet of drug administration, as it is cheaper andbetter adapted to patient comfort. However, oral route is still inaccessible to many drugssuch as biologics and biosimilars respectively certain anticancer drugs and antiretrovirals(ARV).The aim of this present study was to find new drugs enhancers that improve the oralbioavailability of drugs and xenobiotics. All the studies were realized in vitro using Ussingchambers technic. To achieve the set objective we used the strategy to develop drugenhancer which can modulate at the same time transcellular and paracellular pathways.In the first part of this study (patent) we have shown that the use of a pharmaceutical and /or a dietetic formulation containing a plant extract (Hibiscus sabdariffa) could increase thebioavailability in vitro in rats not only of cisplatin (21 fold), oxaliplatin (11 fold) andFluorescein Isothiocyanate-Dextran 4000 (FD4, 3 fold). All that drugs were transportedthrough intestinal barrier using paracellular pathway. In addition the study showed thatthis formulated enhancer can increased the bioavailability of Efavirenz (7 fold) andAtazanavir (4 fold) which are active transported.In order to assess the effect of new drugs enhancer on mucus thickness that limits thetransport of xenobiotic through intestinal barrier, we decide to evaluate his effect on passiveand active transport of drugs.In the second part of this study we have shown that after a week of pre-treatment of ratswith Metronidazole (MTZ, publication 1) and Cotrimoxazole (CTX, publication 2), the twomost commonly used antibiotics in the prophylaxis against opportunistic infections in HIV /AIDS, both increase colonic mucus thickness that affect directly passive intestinalpermeability by reducing conductance an index of passive transport through intestinalepithelium. In addition those antibiotics also entail a change in the transepithelialconductance and ARV fluxes. After MTZ and CTX treatment the secretion of Atazanavir(ATZ) increases respectively in the proximal colon by 2 to 4 fold and in the distal colon by 3to 5 fold respectively. Ritonavir (RTV) is poorly absorbed in control, after a week of pretreatmentwith MTZ and CTX one rather notices a secretion of RTV 5 to 10 fold higher in theproximal and 2 to 5 fold higher in the distal colon. The next study will be conducted toevaluate the effect of new drugs enhancer on mucus thickness layer.In conclusion, oral bioavailability of drugs and xenobiotics can be enhanced bypharmaceutical composition that contains herbal extract which increase passive and activetransport of drugs through intestinal barrier
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Mohiddin, Syed Basha. "Development of novel unsupervised and supervised informatics methods for drug discovery applications". Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1138385657.
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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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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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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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McCallum, Emma Clare. "Adaptive phase II clinical trial design using nonlinear dose-response models". Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709013.
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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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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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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/.
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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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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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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.
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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.
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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.
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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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Naina, Mohamed Isa. "Novel approaches to pharmacovigilance : exploiting routinely acquired healthcare data". Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=165979.
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Introduction: The main pharmacovigilance system in the United Kingdom is the ‘Yellow Card’ spontaneous reporting system which suffers from low reporting rate, and long lag time between drug launch and ADR recognition. Aim: The aim of this study is to develop a pharmacovigilance system to permit the early detection of adverse drug reactions using routinely acquired NHS health data with minimal cost and resources. Methods: There are 2 methods for this study; Phase 1: The extraction of drug persistence data from routinely acquired NHS health data, and Phase 2: Identifying the exact reason(s) for patient discontinuation of drug therapy within 6 months of the index prescription. Results: Phase1: During the study period 4243 patients were initiated on ramipril, 8849 patients on simvastatin, 3242 patients on ARBs, 3646 patients on amlodipine and 269 patients on lercanidipine. The 1, 2-3 and 4-6 month discontinuation rates were 9.9%, 4.9% and 4.2% respectively for ramipril, 9.5%, 3.4% and 3.2% for simvastatin, 8.7%, 2.9% and 2.5% for ARBs, 16.2%, 6.3% and 4.8% for amlodipine, and 17.8%, 3.7% and 3.7% for lercanidipine. Drug discontinuation rates determined agree closely with published data from trials and post marketing surveys in terms of the peak time at which ADRs and discontinuations occur (1 month), the populations most frequently affected (females and the young or elderly depending on drug), and the relationship between the frequency of ADRs and discontinuations relative to the drug of interest, especially for antihypertensive (CCBs>ACEIs>ARBs). Phase 2: Six (20%) of 30 participating primary care practices, contributing to the PTI database, agreed to be approached directly. Completed data was returned for 98% of patients whom discontinued amlodipine due to a specific ADR. Conclusions: Drug discontinuation rates obtained from health care databases is a good surrogate for ADR/E rates. Specific reasons for discontinuation, such as adverse drug reactions, can be identified directly from such electronic databases or more effectively from the primary care medical records held in primary care practices.
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Mavridis, Lazaros. "High throughput virtual drug screening using spherical harmonic molecular surface representations". Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=25936.
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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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Bartu, Anne E. "A grounded study of the experience of detoxification from psychoactive drugs". Curtin University of Technology, School of Nursing, 1998. http://espace.library.curtin.edu.au:80/R/?func=dbin-jump-full&object_id=12124.
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The main objective of this thesis was to develop a substantive theory that explained the phenomenon of detoxification from psychoactive drugs such as alcohol, tranquillisers, opioids, and amphetamines in a medical treatment unit for licit and illicit drug users. The other objectives were to (a) determine if the differences reported in earlier studies between licit and illicit drug users in terms of socio-demographic and drug use variables remain extant, and (b) assess the extent of minor psychiatric morbidity among the participants. Both grounded theory and quantitative methods of data collection and analysis were used in the study.The findings of the quantitative component of the study indicated that there were significant differences between licit and illicit drug users in regard to age, drug use characteristics, and completing the treatment program. That is, illicit drug users were younger than licit drug users, more likely to be poly drug users, and drop out of the program. The prevalence of minor psychiatric morbidity among the participants was 93.6%, and was largely independent of socio-demographic and drug use variables. The high prevalence of minor psychiatric morbidity suggests that the majority of participants warranted further follow-up support in the community after they left the treatment unit. The uptake of referrals for follow-up support, however, was 55.9%.The basic or core social psychological problem identified by the constant comparative method of grounded theory was found to have two parts, both of which were interpreted as forms of disequilibrium. The first part of disequilibrium, which was a precursor to treatment, was conceptualised as Hitting the Wall. The events associated with the symbolic "wall" interrupted the participants' drug focussed lifestyles and induced them to enter treatment. These events and problems were not resolved whilst in ++treatment, they lingered with the participants while they were in the unit, and remained to be addressed when they left. Whilst undergoing detoxification the participants encountered the second part of disequilibrium which was categorised as Incompatibility. The problem of Incompatibility was related to the heterogeneity of the participants and the structure of the treatment program that in many cases was unable to accommodate individual differences and needs.The core or basic social psychological process was conceptualised as Seeking Balance through Hanging In. The participants engaged in this process to deal with the disequilibrium of the precursor problem of Hitting the Wall and the problem of Incompatibility encountered in the unit. Seeking Balance through Hanging In was found to have four phases. The phases were Making the Break, Submitting to Cleansing, Fitting In, and Moving On. The process was linear in that the phases were sequential, and failure to complete a phase meant dropping out of the detoxification program. The experience of detoxification was modified by several contextual conditions. These were the physical enviroment, the participants' expectations of withdrawal symptoms, and the workload of the staff.The substantive theory, Seeking Balance through Hanging In, integrated all emergent categories, and explained the experience of the phenomenon of withdrawal from psychoactive drugs in a particular context. Recommendations for further research include testing the described phases and relationships of the substantive theory in similar environments, exploring the importance of the modifying conditions on client outcomes, and undertaking follow-up studies to determine the outcomes of those who completed the program as compared to the outcomes of those who dropped out. In addition, further studies are recommended to assess the transientness of the level ++
of minor psychiatric morbidity detected among the participants in this study.The findings of this study make an important contribution to understanding the experience of detoxification from the perspective of the participants. The substantive theory has implications for clinical practice, professional education, management, and further research.
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Bartu, Anne. "A grounded study of the experience of detoxification from psychoactive drugs". Thesis, Curtin University, 1998. http://hdl.handle.net/20.500.11937/1748.
Pełny tekst źródłaStreszczenie:
The main objective of this thesis was to develop a substantive theory that explained the phenomenon of detoxification from psychoactive drugs such as alcohol, tranquillisers, opioids, and amphetamines in a medical treatment unit for licit and illicit drug users. The other objectives were to (a) determine if the differences reported in earlier studies between licit and illicit drug users in terms of socio-demographic and drug use variables remain extant, and (b) assess the extent of minor psychiatric morbidity among the participants. Both grounded theory and quantitative methods of data collection and analysis were used in the study.The findings of the quantitative component of the study indicated that there were significant differences between licit and illicit drug users in regard to age, drug use characteristics, and completing the treatment program. That is, illicit drug users were younger than licit drug users, more likely to be poly drug users, and drop out of the program. The prevalence of minor psychiatric morbidity among the participants was 93.6%, and was largely independent of socio-demographic and drug use variables. The high prevalence of minor psychiatric morbidity suggests that the majority of participants warranted further follow-up support in the community after they left the treatment unit. The uptake of referrals for follow-up support, however, was 55.9%.The basic or core social psychological problem identified by the constant comparative method of grounded theory was found to have two parts, both of which were interpreted as forms of disequilibrium. The first part of disequilibrium, which was a precursor to treatment, was conceptualised as Hitting the Wall. The events associated with the symbolic "wall" interrupted the participants' drug focussed lifestyles and induced them to enter treatment. These events and problems were not resolved whilst in treatment, they lingered with the participants while they were in the unit, and remained to be addressed when they left. Whilst undergoing detoxification the participants encountered the second part of disequilibrium which was categorised as Incompatibility. The problem of Incompatibility was related to the heterogeneity of the participants and the structure of the treatment program that in many cases was unable to accommodate individual differences and needs.The core or basic social psychological process was conceptualised as Seeking Balance through Hanging In. The participants engaged in this process to deal with the disequilibrium of the precursor problem of Hitting the Wall and the problem of Incompatibility encountered in the unit. Seeking Balance through Hanging In was found to have four phases. The phases were Making the Break, Submitting to Cleansing, Fitting In, and Moving On. The process was linear in that the phases were sequential, and failure to complete a phase meant dropping out of the detoxification program. The experience of detoxification was modified by several contextual conditions. These were the physical enviroment, the participants' expectations of withdrawal symptoms, and the workload of the staff.The substantive theory, Seeking Balance through Hanging In, integrated all emergent categories, and explained the experience of the phenomenon of withdrawal from psychoactive drugs in a particular context. Recommendations for further research include testing the described phases and relationships of the substantive theory in similar environments, exploring the importance of the modifying conditions on client outcomes, and undertaking follow-up studies to determine the outcomes of those who completed the program as compared to the outcomes of those who dropped out. In addition, further studies are recommended to assess the transientness of the level of minor psychiatric morbidity detected among the participants in this study.The findings of this study make an important contribution to understanding the experience of detoxification from the perspective of the participants. The substantive theory has implications for clinical practice, professional education, management, and further research.
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Baker, Nicola Louise. "Screening for new natural drugs and drug resistance determinants in African trypanosomiasis". Thesis, London School of Hygiene and Tropical Medicine (University of London), 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590629.
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Soane, Robert J. "Bioadhesive polymers as intranasal drug delivery systems for peptide and protein drugs". Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298078.
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Kola-Mustapha, Adeola Tawakalitu. "Novel biomimetic polymeric nanoconjugates as drug delivery carriers for poorly soluble drugs". Thesis, De Montfort University, 2013. http://hdl.handle.net/2086/10243.
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Active Pharmaceutical Ingredients with poor solubility have presented significant difficulties in drug product design and development including slow and ineffective absorption leading to inadequate and variable bioavailability. Therefore it has become increasingly desirable to overcome the low aqueous solubility of drug candidates and develop more novel and innovative formulation approaches to increase the dissolution rate of the poorly soluble drugs. This work focuses on the formulation of novel amorphous ibuprofen-polymer nanoconjugates based on the polymer-drug complexation in order to improve its physical and dissolution characteristics without the use of toxic organic solvents. Plain and ibuprofen-loaded binary and ternary nanoconjugates were prepared using four modified co-precipitation techniques including melt solubilization; alkaline solubilization; surfactant solubilization and hydrotropic complexation techniques. A remarkably high loading capacity was achieved ranging from 89.05 to 99.49% across the four techniques and polymer-polymer ratio of 50:50 was found to be most efficient. All the four techniques reduced the size of ibuprofen (2.87 μm) significantly in the presence of 2.0 x10-3 mM of Diethylaminoethyl Dextran (DEAE-Dextran) in the order melt solubilization (203.25 nm) > alkaline solubilization (185.68 nm) > surfactant (Tween 80) solubilization (122.17 nm) > hydrotropic complexation (77.92 nm). 5.0 x 10-4 mM of chitosan also reduced the size of ibuprofen from 2872.12 to 10.70 nm (268-fold reduction). The FTIR spectroscopic analysis revealed electrostatic, hydrophobic and hydrogen bonding interaction between solubilized ibuprofen and the cationic polymers (DEAE-Dextran and chitosan) to form a new product (an amide). Polymer-polymer complexation also occurred between DEAE-Dextran and gellan as well as chitosan and gellan to a different extent depending on the mixing ratios. 1H and 13C NMR analysis confirmed the conjugation between ibuprofen and each of the cationic polymers as well as the formation of a new amide product. DSC thermal analysis showed that the nanoconjugates exhibited new broad and diffuse peaks confirming that they did exist in amorphous state as multiple complexes. The TGA thermograms of the binary nanoconjugates exhibited one step degradation profile compared with the physical mixture which exhibited two steps. However the ternary nanoconjugates exhibited two steps degradation profile confirming the formation of multiple complexes. Marked enhancement of drug release was achieved by the four techniques compared with the ibuprofen control. All the DG (DEAE-Dextran - Gellan) complexes exhibited a higher release profile than ibuprofen control. Fickian and non-Fickian anomalous mechanisms were deduced for the drug release of ibuprofen from the binary conjugates. The ternary nanoconjugates exhibited non-Fickian (anomalous) diffusion, Fickian diffusion and Super Case II transport release mechanisms. The ternary nanoconjugate hydrogels exhibited complete release (100%) within 48 h. The lowest concentration of DEAE-Dextran, Gellan - Ibuprofen - DEAE-Dextran (GIbDD) 2:0.125, increased the release of ibuprofen by 13.4% however higher concentrations of DEAE-Dextran decreased the release profile steadily. It was concluded that DEAE-Dextran has potentials in the formulation of modified (extended) release of ibuprofen. The most prominent mechanism of release of ibuprofen from the nanoconjugate hydrogel was Super Case II transport. SEM and AFM micrographs of the drug loaded composite pharmaceutical films exhibited concentric spheres with two and three layers for the binary and ternary films respectively. This supports the evidence of internalization of ibuprofen by the polyelectrolyte complex. The FTIR and DSC results confirmed electrostatic and hydrophobic interactions between ibuprofen and DEAE-Dextran as well as between gellan and DEAE-Dextran. Thermal analysis revealed that plain bilayer films were thermally more stable than composite films. The addition of ibuprofen significantly increased (p < 0.05, n = 4) the swelling ratio of the films compared with films without the drug. The drug loaded bilayer films exhibited Fickian diffusion mechanism while the dominating mechanism for composite films was anomalous (Non-Fickian) transport. From the foregoing, it was evident that ibuprofen-polymer nanoconjugate present a novel tool for the delivery of ibuprofen with potential application for transdermal delivery.
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Sostelly, Alexandre. "Mechanistic model-based drug development in the management of anticancer drugs resistance". Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10203.
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La résistance aux chimiothérapies anticancéreuses constitue un problème majeur dans la prise en charge du cancer. Les transporteurs d'efflux contribuent à ce phénomène de résistance en altérant l'accumulation intracellulaire des cytotoxiques. Dans le passé, l'inhibition du transporteur d'efflux P-gp n'a pas permis de surmonter ce phénomène notamment à cause du manque de méthodes adéquates pour identifier et quantifier la pharmacologie des inhibiteurs d'efflux. Récemment de nouveaux inhibiteurs de BCRP, l'un des derniers transporteurs d'efflux découverts, ont été synthétisés permettant de retester l'intérêt de l'inhibition de ces transporteurs dans la prise en charge de la résistance aux anticancéreux. Néanmoins, afin d'éviter les mêmes écueils que lors du développement des inhibiteurs de P-gp, il est nécessaire d'utiliser d'autres approches telles que la modélisation mathématique dès le début du développement préclinique de ces inhibiteurs. Cette thèse a pour but de montrer les bénéfices de la modélisation et de la simulation dans le développement préclinique des inhibiteurs de transporteurs d'efflux et plus largement dans le développement des molécules anticancéreuses. L'exemple utilisé au travers de ce travail concerne l'étude de l'interaction entre l'irinotecan, un cytotoxique largement utilisé dans le traitement du cancer colorectal, et le MBLI87, un nouvel inhibiteur de BCRP. Deux principaux axes ont été abordés dans ce travail : - Le développement de modèles (semi-) mécanistiques à effets mixtes pour identifier et quantifier les facteurs impactant l'efficacité de la combinaison irinotecan-MBLI87 - Le développement de modèles d'inhibition de la croissance tumorale à effets mixtes pour évaluer précocement ce type d'interaction de traitements et pour optimiser la réponse tumorale. Les résultats obtenus avec l'approche de modélisation ont permis d'identifier certains des mécanismes tumoraux impactant l'efficacité des inhibiteurs de transporteur d'efflux. De plus cette approche s'est révélée supérieure aux approches classiques dans l'évaluation de ces molécules et dans l'optimisation de la réponse tumorale démontrant la puissance de la modélisation et de la simulation comme outil de développement des molécules anticancéreusesAnticancer drug resistance is a major issue in the management of cancer disease. Efflux transporters contribute to the multidrug resistance by altering the intracellular disposition of cytotoxic drugs. In the past, the inhibition of P-gp efflux transporter essentially failed because of the lack of adequate methods to identify their mechanisms of action. Recently, new inhibitors of BCRP, one of the latest efflux transporter that have been discovered, have been developed that allow re-testing the multidrug resistance inhibition through efflux inhibition. Nevertheless, to avoid the same issues of development as for P-gp inhibitors, new methods have to be used. This PhD work aims to demonstrate the benefits of mechanistic models to support the development of efflux transporter inhibitors and more generally of oncology compounds through two axes: - The development of mechanistic models of the interaction between cytotoxic and efflux transporter inhibitors - The development of quantitative tumour growth inhibition models to early evaluate oncology compounds and optimize patients’ response The results obtained with this approach allow the identification of key mechanisms of efflux transporter inhibitors and demonstrate the power of modelling and simulation to support oncology drug development
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Moorad, Razia. "Computer-aided drug design and the biological evaluation of anti-cancer drugs". Doctoral thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/20715.
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Computer-aided drug design has become a promising alternative to high-throughput screening by identifying potential hits in silico for in vitro evaluation. In this study a combination of ligand-based and structure-based virtual screening was performed to identify in silico hits. This was based on finding similar inhibitors to 6-amino-4-(4-phenoxyphenylethylamino) quinazoline, a potent inhibitor of the Nuclear Factor kappa B (NF-κB), a transcription factor that has a pivotal role in cancer survival and Pentamidine, an anti-parasitic drug that has recently been demonstrated to possess tumour-killing activity. A hierarchical methodology consisting of a similarity search followed by structure-based virtual screening of the ZINC database was performed. In order to perform the docking studies, binding sites for 6-amino-4-(4-phenoxyphenylethylamino) quinazoline on the NF-κB/IκBα complex were identified through blind docking. In addition, the National Cancer Institute (NCI) database was screened, utilising existing structure-activity relationship data from literature. A pharmacophore search was designed to test the hypothesis of the structural features necessary for activity as seen with quinazoline inhibitors of NF-κB. No virtual hits from the ZINC database were confirmed with in vitro activity. On the other hand, three compounds identified from the pharmacophore search were confirmed to inhibit cancer cell proliferation in vitro, with compound NSC727152 demonstrating the most potent activity. In order to determine if NSC727152 acted similarly to 6-amino-4-(4-phenoxyphenylethylamino) quinazoline by inhibiting NF-κB, the effects of NSC727152 on the expression of NF-κB targeted genes, including the Growth Arrest and DNA Damage 45 (GADD45) α and γ and the Interleukin 6 (IL-6) genes were evaluated. GADD45 α and γ have been shown to be regulated by NF-κB during cancer progression and aberrant IL-6 gene expression has been implicated in cancer progression and mortality and its expression is at least partially mediated via constitutive activation of NF-κB. In this study, it has been demonstrated that GADD45 α and γ are upregulated after treatment with NSC727152. A down-regulation of the IL-6 promoter activity and mRNA expression in cancer cells treated with NSC727152 has also been demonstrated in this study. However, no hits similar to Pentamidine were confirmed with in vitro activity. In conclusion, the compound NSC727152 has been shown to inhibit NF-κB and further analysis is necessary to determine its full potential as an NF-κB inhibitor.
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Coomber, Ross. "Perceptions of illicit drugs and drug users : myth-understandings and policy consequences". Thesis, University of Greenwich, 1999. http://gala.gre.ac.uk/8648/.
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This submission to the University of Greenwich for a Ph.D. by published works is composed of ten peer-reviewed articles, five book chapters, and one journal editorial. The earliest publication is dated from 1992 while the two most recent articles have been formally accepted for publication and are to be published in the near future. The pieces, to aid coherence, are not arranged in strict chronological order but rather in an order best able to demonstrate coherence and theme. The central theme running through these published works relates to the ways that drugs, drug users, and the activities which surround them are often subject to exaggeration, distortion and untruths and that drug control policy, rather than being rationally based is often the result of fear, prejudice and unreason. The core of the submission, eight papers researching the dangerous adulteration of illicit drugs, reflects these issues strongly. An area almost untouched by social science prior to this research these papers represent an attempt to pull together a range of evidence to inform more fully about drug adulteration practices. A wide range of methods, including a relatively innovative approach to researching hard to reach groups via the Internet and World Wide Web were employed. Almost all of the findings are at odds with what is commonly and professionally (drugs field) assumed to happen as regards the adulteration/dilution of illicit drugs. The other contributions all reflect similar concerns but are focussed on other drug related areas. Each piece is preceded by a short contextualising introduction. The appendices include a complimentary unpublished paper on drug adulteration, the preface to one of two books to which I was sole editor, some shorter contributions to drug field publications which, whilst widely read are less academic in their tone and approach, and two publications which represent the culmination of earlier joint research on drug policy.
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PELLIZZONI, ELENA. "Molecularly imprinted polymeric nanoparticles for the therapeutic drug monitoring of anticancer drugs". Doctoral thesis, Università degli Studi di Trieste, 2016. http://hdl.handle.net/11368/2907991.
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La chemoterapia consiste nell’impiego di uno o di una combinazione di farmaci antitumorali per il trattamento del cancro. Tuttavia tali farmaci sono caratterizzati da una famacocinetica molto variabile e da una elevata tossicità che porta alla comparsa di molti effetti indesiderati nei pazienti, diminuendo l’efficienza della terapia. In questo contesto l’impiego del “Therapeutic Drug Monitoring” (TDM) risulta particolarmente importante in quanto permette per lo sviluppo di terapie personalizzate per i pazienti aumentando l’efficienza della terapia e la qualità della vita dei pazienti.
Questo progetto è finalizzato alla sintesi e allo sviluppo di sensori, basati su nanoparticelle polimeriche ad impronta molecolare, per i farmaci antitumorali: sunitinib, paclitaxel, SN38 e irinotecano, suo profarmaco.
Tali nanoparticelle solubili sono state ottenute mediante polimerizzazione radicalica ad elevata diluizione utilizzando diversi monomeri funzionali: N-acriloil-tirosina metil estere, N-acriloil triptofano metil estere, 4-vinilpiridina e 7-acrilossicumarina. La reazione è stata effettuata lasciando interagire i monomeri funzionali e il farmaco mediante interazioni deboli (legami idrogeno, π-staking, interazioni di Van der Waals) in DMSO e dopo l’aggiunta dell’acrilamide come co-monomero, dell’N,N’-etilenebisacrilamide come crosslinker e dell’iniziatore radicalico azobisisobitironitrile (AIBN) la polimerizzazione è stata ottenuta scaldando a 70°C per 4 giorni. La molecola templato è stata rimossa mediante dialisi prima in una miscela di metanolo e acido acetico, e poi in acqua. Le particelle ottenute dopo liofilizzazione, sono state caratterizzate mediante 1H-NMR, Nanosigh e Dynamic Laser Ligh Scattering. La capacità di legame e la selettività dei polimeri è stata studiata mediante test di recupero utilizzando un metodo HPLC per la quantificazione del farmaco catturato. Mentre le proprietà fluorescenti di alcuni dei polimeri sintetizzati sono state utilizzate per studiare le affinità di legame dei polimeri a basse concentrazioni di farmaco.
Il polimero contenente cumarina e specifico per il sunitinib è stato utilizzato come sensore fluorescente per lo sviluppo di un test di validazione in DMSO:plasma. Il sensore ha mostrato un’accuratezza del 15%, una precisione del 10% e una buona robustezza. Inoltre due diversi sensori fluorescenti sono stati sviluppati per la quantificazione dell’irinotecano in metanolo:plasma. Il primo sensore si basa sul quenching della fluorescenza intrinseca dell’irinotecano, mentre il secondo è un polimero molto fluorescente contenente un monomero funzionale con un gruppo naftalimidico la cui fluorescenza è spenta in seguito all’interazione con l’irinotecano.
Inoltre un test fluorimetrico e colorimetrico è stato sviluppato per quantificare il paclitaxel mediante la tecnica del “dye displacement”. Il test infatti, si basa sulla competizione tra il farmaco libero ed il farmaco legato covalentemente al DABCYL per il legame ad un polimero ad imprinting molecolare contenente EDANS come monomero funzionale fluorescente. Infatti il DABCYL è sia un colorante rosso, sia un FRET quencher dell’EDANS, perciò il suo legame nel polimero porta ad una variazione del colore e della fluorescenza del polimero.
Infine un test colorimetrico per la quantificazione dell’irinotecano è stato sviluppato utilizzando un polimero ad imprinting molecolare contenente l’acido 2-acrilamido-2-metil propansolfonico come monomero funzionale. Il test si basa sul legame del colorante: anilina gialla nei siti di legame del polimero rimasti liberi dopo interazione con i campioni di farmaco. L’interazione tra il colorante e l’acido solfonico nel polimero genera un cambio di colore da giallo a rosso.Chemotherapy consists in cancer treatment by the administration of a single or a combination of anticancer drugs. However chemotherapy agents are often characterized by an high variability of pharmacokinetic among patients and an high toxicity that leads to the appearance of many side effects decreasing the therapy efficiency. Therefore the therapeutic drug monitoring (TDM) become useful to develop personalized therapies for patients in order to increase the efficiency of the therapy and patient compliance. This project is aimed on the synthesis and development of specific sensors based on molecularly imprinted polymeric nanoparticles, to be applied in TDM of the anticancer drugs: sunitinib, paclitaxel, SN38 and its prodrug irinotecan. Soluble nanoparticles were obtained by high dilution radical polymerization with different functional monomers: N-acryloyl-tyrosine methyl ester, N-acryloyl-tryptophan methyl ester, 4-vinyl pyridine or 7-acryloyloxy-coumarin. The reactions were carried out allowing the functional monomer to interact with the drug by weak interactions (H-bonds, -staking and Van der Waals) in DMSO and after the addition of the co-monomer acrylamide, the crosslinker N,N’-ethylene bisacrylamide, and the radical initiator azobisisobutyronitrile (AIBN) the polymerization was achieved heating at 70°C for 4 days. The template was removed by dialysis first in methanol:acetic acid mixture and after in water. After the freeze-drying the polymers were characterized by 1H-NMR, Nanosight, and Dynamic Laser Light Scattering. The polymers binding capabilities and selectivity were investigated by rebinding tests using an HPLC method for the quantification of drug captured. while the fluorescence properties of some of these polymers were exploited to study the polymers binding affinities at low drug concentrations. The polymer containing coumarin and imprinted with sunitinib was used as fluorescence sensor to set up a validation test in DMSO:plasma mixture. The system showed an accuracy of 15%, a precision of 10% and a good robustness. Two different fluorescence sensors were also developed for irinotecan able to quantify the drug in methanol:plasma mixtures. The first sensor is based on the quenching of the intrinsic fluorescence of irinotecan, while the second is an highly fluorescence polymer containing a functional monomer with a naphthalimide mojety whose fluorescence is quenched upon interaction with the drug. Moreover the dye displacement technique was used to set up a fluorescent and colorimetric test for paclitaxel quantification. The test is based on the competition between the free paclitaxel and the drug covalently linked to DABCYL dye, for the binding in to an imprinted polymer containing EDANS fluorescent functional monomer. Since DABCYL is both a red dye and a FRET quencher of EDANS, its binding into the polymer gives a change in the polymer fluorescence and colour. Finally a colorimetric test for irinotecan quantification was developed using an imprinted polymer containing 2-acrylamido-2-methylpropane sulfonic acid as functional monomer. The test is based on the binding of aniline yellow dye in to the remaining free binding sites of the polymer after treatment with drug samples. The interaction between the dye and the sulfonic acid in to the polymer gives a change of colour from yellow to red.
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IACUZZI, VALENTINA. "Design of detection systems for the therapeutic drug monitoring of anticancer drugs". Doctoral thesis, Università degli Studi di Trieste, 2020. http://hdl.handle.net/11368/2967986.
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Considerato che la maggior parte dei farmaci antitumorali risulta caratterizzata da un'alta variabilità interindividuale nelle concentrazioni plasmatiche, che si riflette sull'efficacia del trattamento, durante il progetto di dottorato qui descritto sono state sviluppate tecniche per il loro monitoraggio terapeutico (TDM).
In primo luogo, è stato sviluppato, validato e cross-validato un metodo LC-MS/MS per la quantificazione di imatinib (IMA) e del suo metabolita attivo, norimatinib (norIMA), in pazienti affetti da tumore stromale gastrointestinale utilizzando la tecnica del dried blood spot (DBS). Il DBS consente di ridurre costi e tempi di campionamento e migliorare la compliance dei pazienti, poiché l’analisi viene effettuata tramite una goccia di sangue capillare depositata su carta. Da questa gli analiti vengono estratti con MeOH acidificato e l'estratto viene iniettato in un sistema LC (configurato con una cromatografia 2D per la pulizia on-line del campione), accoppiato ad un API-4000QT. Il metodo ha mostrato una buona linearità (R2> 0,996) nei range di 50-7500 ng/mL e 10-1500 ng/mL per IMA e norIMA. La precisione e l’accuratezza intra-day sono state, rispettivamente, ≤3.1% e tra 88.9-112.8%, mentre quelle inter-day erano ≤6,6% e tra 95.7-104.3%, per entrambi gli analiti. Sono stati valutati inoltre: l'influenza dell'ematocrito (Hct), del volume depositato e dell'omogeneità del campione sull’analisi; la correlazione tra la concentrazione in DBS da prelievo venoso e da finger-prick (differenza tra -12 e 3.8%) e la stabilità dei DBSs (fino a 16 mesi). Il metodo è stato applicato per la quantificazione di 67 campioni DBSs di pazienti. Le concentrazioni in DBS, normalizzate per Hct e per un fattore di correzione che prescinde dall’Hct, correlano con quelle plasmatiche.
Parte del lavoro di questo progetto è stato anche dedicato allo sviluppo di strategie alternative a LC-MS/MS per favorire ulteriormente l’applicazione del TDM. In particolare, è stata eseguita la sintesi di polimeri (molecularly imprinted polymers - MIPs), con l'obiettivo futuro di applicarli come recettori in un sistema di rilevamento fluorimetrico per IMA. I MIPs sono stati sintetizzati sfruttando l'approccio non covalente e la polimerizzazione radicale ad alta diluizione. Tramite questa tecnica, i MIPs ottenuti, sintetizzati in DMSO e con acido metacrilico come monomero funzionale, presentano dimensioni nanometriche (dati acquisiti tramite dynamic light scattering). I tests di rebinding hanno dimostrato che solo 2 MIPs sono stati in grado di legare IMA con una buona specificità (rispetto ai corrispondenti polimeri non-imprinted) e selettività.
È stato infine sviluppato e validato un metodo LC-MS/MS per la quantificazione di ribociclib (RIBO), palbociclib (PALBO) e letrozolo (LETRO) in plasma. RIBO e PALBO sono farmaci appartenenti alla famiglia dei CDKIs recentemente approvati per il trattamento del carcinoma mammario in combinazione con LETRO. Il metodo messo a punto risulta adatto per l’applicazione nella pratica clinica, grazie ad una semplice preparazione del campione e ad una rapida analisi (6.5 min). Il metodo risulta lineare (R2 tra 0.992-0.983) nei range di concentrazione di 0.3-250 ng/mL per PALBO, 10-10000 ng/mL per RIBO e 0.5-500 ng/mL per LETRO (che coprono le concentrazioni plasmatiche terapeutiche). La precisione e l’accuratezza intra-day sono state, rispettivamente, ≤3.6% e tra 94.5-112.3% per tutti e gli analiti, mentre quelle inter-day erano rispettivamente ≤7.3% e tra 94.5-112.9%. Il metodo è stato applicato con successo alla quantificazione di campioni plasmatici di pazienti.
In conclusione, con lo sviluppo di queste strategie si spera di implementare l’utilizzo del TDM per i farmaci oncologici nella pratica clinica.Despite the continuous progress in drug therapy, most anticancer drugs appear to be characterized by a high interindividual variability in plasma concentrations that is reflected in the efficacy of the treatment. From this arises the need of a personalized approach, so that the drug concentrations in plasma are adequate in each patient. On this basis, during the PhD project reported hereby, different techniques for therapeutic monitoring (TDM) of anticancer drugs were developed. First, a LC-MS/MS method for the quantification of imatinib (IMA) and its active metabolite, norimatinib (norIMA), was developed, validated and cross-validated in patients affected by gastrointestinal stromal tumour. This method allows to perform the quantification directly on a drop of capillary blood, exploiting the dried blood spot (DBS) technique, reducing sampling time, costs and improving patients’ compliance. Analytes were extracted from DBS samples by adding acidified methanol and the extract is injected into a LC system (configured with a 2D chromatography for online cleaning of the sample), coupled with an API-4000QT. The method showed good linearity (R2> 0.996) in the ranges of 50-7500 ng/mL and 10-1500 ng/mL for IMA and norIMA. Intra-day precision and accuracy were ≤3.1% and between 88.9-112.8%, respectively, while inter-day ones were ≤6.6% and between 95.7-104.3 %, for both analytes. Moreover, were also evaluated: the influence of the haematocrit (Hct), of the spot size and of the sample homogeneity on the analysis; the correlation between the concentration in DBS from venous sampling and from finger-prick (% difference between -12 and 3.8%) and the stability of DBSs (up to 16 months). Then, the method was applied for the quantification of 67 DBSs patients’ samples. Good agreement was obtained between IMA and norIMA concentrations found in DBS and plasma samples applying either the Hct normalization or avoiding it, simply multiplying the DBS concentration with a correction factor. Part of the work of this project was also dedicated for the development of alternative strategies for the quantification of anticancer drugs, to promote the application of TDM. In particular, the synthesis of molecularly imprinted polymers (MIPs) was performed, with the future goal of applying them as receptors in a fluorimetric detection system for IMA. MIPs were synthesized using the non-covalent approach and high dilution radical polymerization. Through this synthesis, the MIPs obtained, synthesized in DMSO with methacrylic acid as functional monomer, shown nanometric size (data acquired by dynamic light scattering). The rebinding tests then showed that 2 MIPs in particular were able to bind IMA with a good specificity (compared to the corresponding non-imprinted polymers) and selectivity. Finally, a LC-MS/MS method was developed and validated for the quantification of ribociclib (RIBO), palbociclib (PALBO) and letrozole (LETRO) in human plasma. RIBO and PALBO are drugs belonging to the CDKIs family, recently approved for breast cancer treatment in combination with LETRO. The method developed is suitable for its application in clinical practice, thanks to simple sample preparation and rapid analysis (6.5 min). The method showed a good linearity (R2 between 0.992-0.983) in the concentration ranges of 0.3-250 ng/mL for PALBO, 10-10000 ng mL for RIBO and 0.5-500 ng/mL for LETRO (covering the therapeutic plasma concentrations). Intra-day precision and accuracy were ≤3.6% and between 94.5-112.3% for all and analytes, respectively, while inter-day ones were ≤ 7.3% and 94.5-112.9%. The method has been successfully applied for patients’ plasma samples quantification. In conclusion, with the development of these strategies there is the hope to implement the application of TDM for anticancer drugs in the clinical practice.
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Stephen, Linda J. "Antiepileptic drugs - treating populations". Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/2005/.
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Epilepsy affects 50 million people world-wide. Since 1982, the Western Infirmary Epilepsy Unit has provided a specialist service for over 6900 people with suspected and established seizure disorders. The twelve studies detailed in this thesis discuss the management of epilepsy in different patient populations, and explore beneficial and adverse effects of antiepileptic drugs (AEDs). AED development has allowed advances in pharmacological treatment of localisation-related epilepsies. Thus, outcomes were investigated in 550 such patients followed-up at the epilepsy clinic over 13 years (Paper i). Of these, 312 (57%) became seizure-free on medication. Those with hippocampal sclerosis had the poorest outcome (p<0.01), and a higher incidence of febrile convulsions (p<0.001). Although many patients benefited from AED therapy, results may be biased, given this cross-sectional study analysed data from both newly diagnosed patients, and those with drug-resistant seizures. Many people with epilepsy take more than one AED, although supportive evidence is sparse. Hence, polytherapy outcomes in 2881 patients registered with the Epilepsy Unit database were examined (Paper ii). Of these, 1617 (56%) were seizure-free, with 332 (21%) taking more than one AED (287 on two, 86%; 42 on three, 13%; 3 on four, 1%). There were 40 duotherapy and 28 triple therapy combinations resulting in seizure freedom. Therefore, combining two or three, but rarely four AEDs may be useful for patients not responding to monotherapy. Because this was a retrospective analysis of newly treated patients and those with refractory epilepsy, the analysis was subject to bias. Lack of a control group was also a weakness. Epilepsy Unit staff are therefore now examining similar outcomes in a large population of newly treated patients only. To establish the place of recently marketed AEDs in clinical practice, four studies examined prospectively the efficacy and tolerability of the novel agent, topiramate, in uncontrolled epilepsy. Adjunctive topiramate was administered in 170 patients with refractory seizures (Paper iii). Seizure frequency and adverse events were monitored. Patients were followed-up until seizure freedom for ≥ 6 months, ≥ 50% or <50% seizure reduction, intolerable side-effects, or lack of efficacy occurred. Seizure freedom was achieved in 39 (23%) patients. A ≥50% reduction in seizure frequency was reported in 80 (47%) others. Doses were often lower than those in regulatory studies. Efficacy as monotherapy was also demonstrated. Using the same end-points, topiramate was added to AED regimens of 64 patients with learning disabilities and epilepsy (Paper iv). Remission from seizures was established in 16 (25%). In similar fashion, levetiracetam was started in 156 patients with uncontrolled epilepsy (Paper v). Of these, 40 (26%) became seizure-free, many on low doses. When the drug was added to AED regimens in 64 patients with learning disabilities, 24 (38%) became seizure-free for at least 6 months (Paper vi). Caregiver quality-of-life scores improved significantly with levetiracetam (p<0.001). It is important to recognise that for all four audits results may be biased due to their observational nature, and the fact that they were undertaken at a single centre, with no control group. For patients with learning disabilities, small numbers, and retrospective baseline recordings for some could also have introduced bias. In Papers vii, viii and ix, findings from longitudinal studies in teenagers, people with learning disabilities and epilepsy, and newly diagnosed elderly patients attending the Epilepsy Unit, are reported. At the Teenager Clinic, 301 adolescents were reviewed over four years (Paper vii). Epilepsy was excluded in 135 (45%), five taking AEDs. A single seizure occurred in 22 others. In the 144 with epilepsy, seizure freedom for ≥ 12 months was attained in 76 (53%), but outcomes were poorer than expected. Neuroimaging was abnormal in 27 (43%). Newly diagnosed patients fared better than those taking treatment (p<0.05). More teenagers with primary generalised seizures (60%) attained remission, compared to those with focal-onset seizures (46%) (p<0.02). The retrospective natures of the analysis, and lack of control group may have biased results, thus making statistical conclusions inaccurate. Findings suggested the need for improved services. Over four years, 214 patients with learning disabilities and refractory epilepsy were followed-up (Paper viii). Although it is generally thought these individuals’ seizures are difficult to control, 59 (43%) became seizure-free for ≥ 12 months with AEDs. There was no change in quality-of-life scoring during this time, and no relationship between extent of learning disability and seizure control. The observational nature of the audit, and lack of control group may have biased results. Currently, there are few data on elderly people with epilepsy. Thus, outcomes over a 20-year period in 117 newly diagnosed senior citizens were examined (Paper ix). After starting AED treatment, 93 (79%) became seizure-free for ≥ 12 months, 73 (62%) with their first drug. Prognosis was better than in younger patients, and for those with fewer pre-treatment seizures (p=0.0078). Again bias may have been introduced because of the study’s observational nature and lack of control group. The final studies concentrate on AED-related adverse effects (Papers x, xi and xii). Bone changes have been reported with AED use. Hence, the relationship between bone mineral density, and long-term AED treatment in 78 older adults (47 post-menopausal women, 31 men), taking hepatic enzyme-inducing or non-inducing AEDs, was explored in a case-controlled study (Paper x). Men had significantly lower bone mineral density than controls at the lumbar spine (p<0.01), and neck of femur (p<0.005). Women had statistically reduced bone mineral density at the femoral neck (p<0.05). It was concluded that long-term AED treatment is an independent risk factor for reduced bone mineral density in people with epilepsy. As sodium valproate may be associated with metabolic changes and polycystic ovarian syndrome, hormone profiles were compared in 76 young men and women taking sodium valproate or lamotrigine monotherapy, to assess whether a pharmacological effect of valproate was responsible (Paper xi). Results revealed only four obese females exhibiting biochemical characteristics of polycystic ovarian syndrome (p=0.05), with obese patients of both sexes (p=0.01), and valproate-treated men (p=0.03) having higher insulin concentrations. Results are not significant when corrected for multiple comparisons. It can therefore be concluded that no differences in metabolic indices between patients taking sodium valproate or lamotrigine existed. To examine further effects on androgenic hormones, and the efficacy and tolerability of sodium valproate and lamotrigine monotherapy, a randomised, prospective study in 225 patients was performed (Paper xii). Patients were recruited if they presented with a minimum of two unprovoked seizures of any type, or a single seizure and underlying neuropathology. Of patients with partial-onset seizures, 81 received sodium valproate and 80 were randomised to receive lamotrigine. Of those with idiopathic generalised epilepsies, 30 received sodium valproate and 34 took lamotrigine. Seizure-free rates were identical in both arms at twelve months between the valproate and lamotrigine cohorts. There was a trend towards superiority for valproate (57% seizure-free) over lamotrigine (35% seizure-free) for patients with idiopathic generalised epilepsies (p=0.09), but a converse separation of outcomes for localisation-related epilepsies (43% seizure-free with valproate, 53% seizure-free with lamotrigine, p=0.24). More patients taking sodium valproate withdrew due to adverse events (p=0.046), eight because of weight gain.
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Li, Jian. "Ciliotoxicity of intranasal drugs". Thesis, Queen's University Belfast, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317473.
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Ridout, G. "Percutaneous absorption of drugs". Thesis, University of Nottingham, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373320.
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Walker, Teneille. "Therapeutic Drugs in Cancer". VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1722.
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The first study examined the interaction between low doses of the multi-kinase inhibitor sorafenib and the histone deacetylase inhibitor vorinostat in colon cancer cells. Sorafenib and vorinostat synergized to kill HCT116 and SW480 cells. In SW480 cells, sorafenib+vorinostat toxicity correlated with CD95 activation and CD95-stimulated autophagy. Drug lethality in SW480 cells was blocked by knock down of CD95. In SW620 cells that are patient matched to SW480 cells, sorafenib+vorinostat toxicity was significantly reduced that correlated with a lack of CD95 activation and lower expression of ceramide synthase 6 (LASS6). Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and tumor cell killing, whereas knock down of LASS6 in SW480 cells suppressed CD95 activation. In HCT116 cells, sorafenib+vorinostat did not increase CD95 plasma membrane levels, weakly induced caspase 8 association with CD95, and knock down of CD95 enhanced drug lethality. In HCT116 cells sorafenib+vorinostat treatment caused CD95-dependent autophagy that was a protective signal. Thus, treatment of tumor cells with sorafenib+vorinostat activates CD95 that promotes viability via autophagy or degrades survival via extrinsic or intrinsic pathways. Drug-induced activation of the de novo ceramide synthesis pathway plays a key role in CD95 activation. The second project explores the mechanism by which the combination of 17AAG, an hsp90 inhibitor, and PD184352, a MEK1/2 inhibitor alters survival in colon cancer cells. 17AAG and PD184352 synergized to kill HCT116 and SW480 cells. In HCT116 cells drug-exposure increased CD95 plasma membrane levels In SW620 cells, 17AAG and PD184352 toxicity was significantly reduced that correlated with a lack of CD95 activation and lower expression LASS6. Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and tumor cell killing. In Mia Paca2 cells, a pancreatic cell line, inhibition of caspase 8 or overexpression of c-FLIP-s suppressed cell killing by PD184352 and 17AAG exposure. Drug lethality in Mia Paca2 cells was blocked by knock down of CD95. Additionally, overexpression of Bcl-xL or knockdown of caspase 9 decreased cell killing in 17AAG and PD184352 combination treatment. Thus, 17AAG+PD184352 exposure activates the extrinsic and intrinsic apoptotic pathways to kill Mia Paca2 cells. This document was created in Microsoft Word 2000.
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Williams, Kylie Anne. "Pharmacoepidemiology of nonprescription drugs". Thesis, The University of Sydney, 1998. https://hdl.handle.net/2123/27671.
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Background: In recent years there have been trends towards increased use of. nonprescription medicines and a greater number of products being switched from prescription-only to nonprescription status. When used properly nonprescription products can be safe and effective treatments, however it is not clear that patients do actually use these products in an appropriate
manner. Despite this, there is currently only low level monitoring of nonprescription medicines to assess their use, efficacy and safety under actual clinical conditions of use.
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Menjoge, A. R. "Enhancing bioavailability of drugs". Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2006. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/2512.
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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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Joshua, Isaac B. "The impact of an intervention program for the treatment of malaria in children in Papua New Guinea". Thesis, Curtin University, 2003. http://hdl.handle.net/20.500.11937/2339.
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Malaria is more prevalent today and the death toll is on the increase annually. It is one of the leading causes of morbidity and mortality worldwide and most of these deaths are in the poorest regions of the world. About 500 million cases are reported annually with more than 2 million deaths, and most are children. It is the major killer in the tropics and a major public health problem in developing countries and Papua New Guinea (PNG) is no exception. Resistant strains have been reported. This may be enhanced by inappropriate human behaviour in the use of anti-malarial drugs. Human factors include inappropriate prescribing and patient behaviour in using anti-malarial drugs. Despite the establishment of the standard treatment guidelines for malaria in PNG, three out of every four patients have chloroquine-resistant falciparum malaria and malaria remains a major health problem. The aim of this study was to evaluate the influence of an education program on patients carers' understanding and effective use of anti-malarial drugs for the treatment of uncomplicated malaria in children in general health clinics in PNG. The trial design involved a pre-post intervention study with a control group. The study was undertaken in the National Capital District. Papua New Guinea using one Clinic as the intervention site and another as the control site. The two clinics were similar in characteristics as confirmed in the study by demographic data where there were no significant differences observed. The data collection took placed over the period February to April 2002. It included observation of drug provision at study sites and interviews of patient carers on the first day at the clinic and a follow up seven days later. Three questionnaires were developed to evaluate the process and outcomes of malaria drug treatment in the above health facilities.Prescribing data were collected from prescriptions and patient carers' interviewed prior to the intervention program. Following the provision of drug information to patient carers. similar drug information and compliance questioning was undertaken. Differences in the pre-post elements of the study and in the control group over the study period were evaluated using Chi-Squared, Kruskal-Wallis, Fisher's Exact or Student's t-tests as appropriate. In excess of 100 patients in the pre- and in the post intervention phases were evaluated for their understanding and effective use of the anti-malarial drugs. In addition, 100 clients were in the control group at another clinic. Patients had attended the clinic up to 8 times in the previous year with a median of 2 visits. Amodiaquine, Fansidar, albendazole and paracetamol made up a total of 60% of the drugs prescribed. The use of medicines was strongly supported with 94.4% indicating no problems with the medication. Only 3% of patients received herbal or local remedies for malaria treatment. 1n patients 10 years or less or their carers, it was found, there was a significant improvement in the carers understanding of the medications. There was a statistically significant improvement in patient outcomes from 57.9% to 92.3% reported as cured following the intervention program. The study has also identified low levels of appropriate administration of antibiotic suspensions in children by patient carers.For example, incorrect responses recorded for amoxycillin suspension were 80.8% (143). Septrim tablets 92% (23), Septrim suspension 86% (123), erythromycin suspension 100% (26), and chloramphenicol suspension 84.4% (38). In this study the face to face (one-to-one) education program was used to influence patient carers understanding and effective use of drugs. The intervention program involved advising, informing, encouraging, and counselling the patient carers verbally on the appropriate and effective use of medicines. The verbal message was reinforced by a suitable label typed in English and Pidgin-English where instructions were clear, simple and unambiguous. The label was then attached to the envelopes or containers containing the drugs. On feedback, the information on the understanding and effective use of drugs was re-emphasized to the carers to reinforce their understanding for future references. Results showed that the intervention program made an impact in improved patient carers understanding and effective use of drugs and children's health outcomes. In conclusion, it is evident that a patient intervention program designed to improve the dosages and frequency of administration of anti-malarial drugs in PNG had no statistically significant outcome. This may be because the current level of understanding was quite high (>70%) and the study experienced a ceiling effect. However, as shown in the results, the patient carers understanding on the appropriate and effective use of drugs was lower during the pre-intervention and control group.When compared clinic-pre with clinic-post, there was a significant difference (P < 0.05) in the cured group and the improved cure rate increases from 57.9% to 92.3%. When compared control pre with control post groups, there was no significant difference (P > 0.05) in the cured group. Therefore, the study identified an improvement in patient outcomes with respect to malaria. Hence. the simple intervention program in influencing patient carers understanding of the appropriate and effective use of medications led to a marked improvement in patient outcomes.
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Crispim, Rute Irene Claudio. "Impact of the national drugs politics (NDP) in the access the gratuitous Drugs". Universidade Federal do CearÃ, 2008. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=1907.
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nÃo hÃThis work aims at the investigation of access to medicines free for users of SUS through the National Drug Policy. The database was used to PENAD98/03. In this research used is a model that conceitua access according to the individual use of the public health service, and receiving the medicine free taking into account the characteristics that lead to use those services. Through Logist model by the method of maximum likelihood has been unable to verify that access to free medicines rose between 6% and 9 percentage points five years after the promulgation of the PNM. The descriptive review with respect to the receipt of free product per lane-income, shows that even among users of SUS, those with higher incomes have a lower probability of receiving free medication. And for the carriers of chronic diseases such as diabetes and hypertension, are more likely to receive free medicine. These results show some effectiveness of the public service to reach those who are really in need.
Este trabalho tem como objetivo a investigaÃÃo do acesso aos medicamentos gratuitos para usuÃrios do SUS por meio da PolÃtica Nacional de Medicamentos. A base de dados utilizada foi a PENAD98/03. Nesta pesquisa utilizou-se o modelo que conceitua acesso de acordo com a utilizaÃÃo do individuo ao serviÃo pÃblico de saÃde, e recebimento do medicamento gratuito levando em conta as caracterÃsticas que levam a utilizar esses serviÃos. Mediante modelo Logist atravÃs do mÃtodo de mÃxima verossimilhanÃa foi possÃvel verificar que o acesso a medicamentos gratuitos aumentou entre 6 e 9% pontos percentuais cinco anos apÃs a promulgaÃÃo da PNM. A analise descritiva com relaÃÃo ao recebimento de medicamento gratuito por faixa de renda, mostra que mesmo entre os usuÃrios do SUS, aqueles com maiores rendimentos tÃm uma probabilidade menor de receber medicamentos gratuitos. E para os portadores de doenÃas crÃnicas como diabetes e hipertensÃo estes, tÃm maiores chances de receberem medicamentos gratuitos. Estes resultados demonstram certa eficÃcia do serviÃo pÃblico de atingir aqueles que realmente sÃo mais necessitados.