Thèses : « THERAPEUTICS ACTION »

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Crowley, John J. « Enabling carers to administer depot injections : an action research study ». Thesis, University of Greenwich, 2014. http://gala.gre.ac.uk/11617/.

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This study has its origins in a question posed by a patient diagnosed with a psychotic illness, as to why her husband could not administer depot injection. Following local and national discussion the study aims were; - to explore the elements of risk management involved in enabling carers (supportive persons) to give depot injections - to develop a training package that may be useful for others to use should such a request be made - to establish whether enabling supportive persons to give depot injections would have an effect on the relationship between the user (recipient of the medication) and the supportive person (giver of medication) - to ascertain the views, concerns and attitudes of medical staff (prescribers) and mental health nurses (administrators of depot injections) about enabling carers/relatives (supportive persons) to give depot intramuscular injection medication. An action research study informed by empowerment theoretical perspectives and influenced by recovery philosophies was used to explore the issues about ‘supportive person’ depot administration. Methods used to collect data included case studies, interviews, observation, reflection and three validated evaluation tools. Data were analysed through thematic analysis, and alongside establishing data, relating to the study aims, additional themes i.e. stigma, disclosure, concealment and trust evolved from the data. The study has relevance for clinical practice, policy and service provision. Current government policies promote choice and collaborative working and health and social care staff are encouraged to be responsive to the views of mental health service users and carers in relation to their experiences and expectations of care. Mental health services are being asked to deliver and translate these policies into practice alongside expectations of gainful employment for service users.

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Romero-Canelón, Isolda. « Design and mechanism of action of organometallic anticancer complexes ». Thesis, University of Warwick, 2012. http://wrap.warwick.ac.uk/55211/.

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Since the discovery of cisplatin, numerous attempts have been made to emulate its activity while reducing its collateral toxicity. Coordination complexes based on a wide number of transition metals have been developed in the search for improved bioavailability, selectivity and reduced adverse side-effects. Ruthenium(II) complexes have been widely developed in this field as a viable alternative to platinum chemotherapeutics. This thesis is concerned with the synthesis, characterization and biological evaluation of three series of novel half-sandwich complexes of the general formula [RuII(arene)(X)(YZ)]n+. These piano-stool RuII complexes have been designed as to allow the fine-tuning of their chemical and biological properties. In the first two series, the arene unit has been varied between p-cymene, biphenyl and terphenyl to investigate the correlation between hydrophobicity and antiproliferative activity, while the N,N-imino pyridine chelating ligand, YZ, has been modified to include either a higher number of aromatic units that could allow better DNA intercalation or substituent groups that could affect the overall charge distribution in the complex. Finally, the monodentate ligand, X, is either chloride or iodide. These compounds have been fully characterised by NMR, MS and elemental analysis. Their aqueous behaviour has been investigated together with the extent of 9-EtG binding, as an indication of the possible interaction with nucleobases. The antiproliferative activity of these novel RuII complexes was determined, several of them show promising IC50 values, in the low μM range, against ovarian, colon, lung and breast cancer cell lines, in many cases the activities observed are better than cisplatin. The pathways for cellular accumulation were investigated. Complexes with an I as the monodentate ligand, X, exhibit partial energy-independent uptake. Overall results indicate that the novel RuII complexes synthesised in this thesis are most likely to be multi-targeted and that their mechanism of action depends to a great extent on the nature of the monodentate ligand, X. Two particularly active complexes in these series include the impy-NMe2 ligand as YZ chelate. These have been compared to their isostructural azopyridine analogues and also to their OsII equivalents. In this case, experiments were designed to study the activation of landmark events that lead to apoptosis, allowing contrasting the effects of different metal centres (Ru vs Os), isoelectronic ligands (impy-NMe2 vs azpy-NMe2) and monodentate ligands (Cl vs I). Results indicate that the molecular pathway followed by the iodido complexes is p53-independent. In comparison, the chlorido analogues activate the intrinsic apoptotic pathway and their activity relies on the existence of this tumour suppressor. DNA intercalation was also evaluated as a possible mechanism of action. Finally, the third series includes inactive RuII complexes with tetrahydroquinoline derivatives, which were found to enhance the activity of platinum drugs in clinical use. These promising preliminary results in the use of RuII complexes in combination therapy open a world of possibilities for the dose-reduction of platinum-chemotherapeutics.

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Vieira, Goncalves Leonam. « Mechanisms of virucidal action of alcohol and metallic ions against nonenveloped viruses ». Thesis, Cardiff University, 2018. http://orca.cf.ac.uk/111705/.

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Studying the mechanism of action (MoA) of biocides against pathogenic microorganisms is crucial to understand their efficacy and limitations, and to develop more efficient microbicidal formulations. Combining alcohol and zinc has been reported to enhance microbicidal activity, but the reasons for such activity are unknown. This study focuses on the impact of combining ethanol and zinc salt at pH 10.5 against nonenveloped viruses. The study is focused on three different aspects: i) virucidal activity screening of ethanol:zinc combinations against bacteriophages and human viruses; ii) impact of ethanol:zinc combinations on virus structure, particularly the viral capsid and nucleic acid, using Transmission Electron Microscopy (TEM); Atomic Force Microscopy (AFM) and agarose gel DNA electrophoresis and iii) chemical speciation and stability of ethanol:zinc combinations over time. The combination of ethanol with zinc salt was found to be more effective against viruses than control formulations containing sole active ingredients and/or excipients only. Activity test of 40%(w/v) ethanol with 0.1% (w/v) zinc salt with excipients (RB- 002 formulation) against F116 and adenovirus type 2 (AdV2) at 60 min contact time yielded 0.68 ± 0.02 and 5.26 ± 0.10 log10 reduction, respectively. In comparison, 0.1% (w/v) zinc salt only with excipient (RB-002G formulation) showed no virucidal activity against bacteriophage F116 (0.14 ± 0.02 log10 reduction) and AdV2 (0.80 ± 0.12 log10 reduction) in suspension. Differences between activities against bacteriophage MS2 and poliovirus type 1 were similar as the ones found between F116 and AdV2. Formulation containing 40%(w/v) ethanol with 0.1% (w/v) zinc salt produced a range of structural damage to F116 and attP AdV5 indicating possible capsid alteration. Effect of the combined formulation on viral capsid was confirmed with AFM with a possible decreased in virus capsid stiffness and significant virus capsid height reduction over 10 min contact time. F116 DNA damage was detected upon exposure to 40%(w/v) ethanol with 0.1% (w/v) zinc salt with excipients, but no damage was detected on AdV2 DNA through electrophoresis analysis. The alcohol/zinc formulation system at pH 10.5 was shown to have promising virucidal activity against non-enveloped viruses at room temperature following an alteration of the viral capsid, and possible damage to the viral nucleic acid. This study also showed the limitations of using bacteriophage as surrogate for mammalian viruses.

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Crisford, Anna. « An investigaton into mode of action and selective toxicity of the novel antiparasitic emodepside ». Thesis, University of Southampton, 2011. https://eprints.soton.ac.uk/338971/.

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Cooper, David L., Derek E. Murrell, David Roane et Sam Harirforoosh. « Effects of Formulation Design on Niacin Therapeutics : Mechanism of Action, Metabolism, and Drug Delivery ». Digital Commons @ East Tennessee State University, 2015. https://dc.etsu.edu/etsu-works/7166.

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Niacin is a highly effective, lipid regulating drug associated with a number of metabolically induced side effects such as prostaglandin (PG) mediated flushing and hepatic toxicity. In an attempt to reduce the development of these adverse effects, scientists have investigated differing methods of niacin delivery designed to control drug release and alter metabolism. However, despite successful formulation of various orally based capsule and tablet delivery systems, patient adherence to niacin therapy is still compromised by adverse events such as PG-induced flushing. While the primary advantage of orally dosed formulations is ease of use, alternative delivery options such as transdermal delivery or polymeric micro/nanoparticle encapsulation for oral administration have shown promise in niacin reformulation. However, the effectiveness of these alternative delivery options in reducing inimical effects of niacin and maintaining drug efficacy is still largely unknown and requires more in-depth investigation. In this paper, we present an overview of niacin applications, its metabolic pathways, and current drug delivery formulations. Focus is placed on oral immediate, sustained, and extended release niacin delivery as well as combined statin and/or prostaglandin antagonist niacin formulation. We also examine and discuss current findings involving transdermal niacin formulations and polymeric micro/nanoparticle encapsulated niacin delivery.

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Ullah, Imran. « A novel in vitro bioluminescence rate-of-kill (BRoK) assay to study the pharmacodynamic properties of antimalarial drug action in Plasmodium falciparum ». Thesis, Keele University, 2016. http://eprints.keele.ac.uk/2411/.

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Massive screens of chemical libraries for antimalarial activity have identified thousands of compounds that exhibit sub-micromolar potency against the blood stage of the malaria parasite Plasmodium falciparum. Triaging these compounds to establish priorities to take forward for development requires additional information regarding their activity. Key amongst their pharmacodynamics (PD) properties is the rate of kill– with a rapid cytocidal effect specifically identified as a key requirement for a Single Exposure Radical Cure and Prophylaxis (SERCaP) product. Compounds that exert an immediate cytocidal effect rapidly reduce parasite burden to ameliorate the morbidity and mortality of disease. With the overall aim to accelerate drug screening by validating a rapid rate of kill, the validation of a novel, quick (6hr) and potentially scalable bioluminescence rate of kill (BroK) assay is described here that demonstrates a good correlation with in vitro recrudescence-based rate of kill data and available in vivo clinical findings. The BRoK assay was used to screen the Medicine for Malaria Venture Malaria Box to identify compounds with rapid cytocidal activity. Seventeen compounds have an initial rate of kill greater than artemisinins, with a further 39 compounds exhibiting a rate of kill between chloroquine and artemisinins. These compounds represent potential Target Candidate Profile, compounds for a SERCaP product. This work highlights the opportunity for the BRoK assay as a hit discovery tool. In addition, the potential for this assay in lead validation through structure activity relationship studies are highlighted.

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Wortley, Michael. « An investigation into the efficacy and mechanisms of action of novel therapeutics for chronic cough ». Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/29125.

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Whilst cough is a defensive reflex, in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) the cough reflex may become exaggerated and unproductive, leading to presentation of chronic cough as a troublesome symptom. Chronic cough is the most common reason that patients seek ambulatory care in the UK, and cough medications are one of the largest segments of the global over-the-counter drugs market, yet there are no cough medications (prescription or OTC) available that are both efficacious AND safe, indicating a large unmet clinical need. β-adrenergic receptor (β-AR) agonists, methylxanthines (theophylline) and fatty acid amide hydrogenase inhibitors (FAAHi) are peripherally acting drugs with a proven safety profile in humans for other uses, but are not currently recognised as anti-tussive medications. This thesis aimed to examine whether these drugs possess anti-tussive activity, and if so, the mechanisms by which they inhibit cough. These drugs were all effective at blocking the in vivo cough response to tussive stimuli in naïve guinea pigs, and in addition β-AR agonists and theophylline inhibited tussive stimulus evoked cough in guinea pigs previously exposed to cigarette-smoke, which display a clinically relevant enhanced cough phenotype. In vitro and in vivo assays of guinea pig vagus nerve/neuron activation were used to show that these compounds inhibit depolarisation of airway-innervating peripheral sensory nerves. Pharmacological and genetic tools were used to investigate the receptors and signalling pathways activated by these drugs. Whilst β-AR agonists, theophylline and FAAHi had different mechanisms of action, a common component was that all three classes of compound act on various potassium channels, thereby reducing the excitability of sensory neurons. This work suggests that drugs that inhibit peripheral sensory nerve activity have the potential to be efficacious as anti-tussives. Specifically the compounds tested have improved clinical side-effect profiles over currently used anti-tussives, and therefore have potential as therapies for chronic cough.

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Sayce, Andrew Cameron. « Iminosugars as dengue virus therapeutics : molecular mechanisms of action of a drug entering clinical trials ». Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:8d4da0ce-bfa6-447d-a280-630479f898af.

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Iminosugars are a class of small molecules defined by substitution of a sugar’s ring oxygen with nitrogen. Various chemical modifications of these basic structures (e.g. alkyl chain addition off of the ring nitrogen) have been developed during the last several decades. These molecules have been considered as therapeutics for a number of pathologies including viral infection, congenital disorders of glycosylation (of both glycoproteins and glycolipids), and diabetes. This thesis focuses on the application of a small subset of iminosugars, known as deoxynojirimycin derivatives, as therapeutics against dengue virus induced pathology. Dengue virus infection predominates in tropical climates, but autochthonous infection has recently emerged in areas of both southern Europe and the southern United States. With 390 million people infected annually, dengue is the most prevalent arthropod-borne viral infection worldwide, and the possibility of severe pathology including haemorrhage, shock, and/or death, necessitates development of effective antiviral therapies. Although the molecular mechanisms responsible for progression to severe dengue disease are not completely understood, there is considerable evidence for the role of both the innate and the adaptive immune responses in development of life-threatening complications. Excessive activation of the innate immune response, a phenomenon known as cytokine storm, has been hypothesised to explain development of symptoms related to vascular permeability, whereas the adaptive immune response has been implicated in severe disease through two hypotheses – the antibody dependent enhancement and original antigenic sin hypotheses. The evidence regarding each of these potential mechanisms of severe pathology is discussed throughout this thesis principally with respect to how iminosugar treatment could alter any detrimental effects of the immune response to dengue virus infection. The principal aim of this thesis is to consider the potential of deoxynojirimycin iminosugars as antiviral therapeutics in dengue infection with a focus on how these molecules exert their antiviral effects in primary human cells. I first consider the contributions of glycoprotein inhibition and glycolipid inhibition on production of infectious dengue virus. These experiments suggest that inhibition of glycoprotein folding is responsible for inhibition of infectious dengue virus production. I next consider the impact of treatment of a promising clinical candidate iminosugar, N9-methoxynonyl-deoxynojirimycin (MON-DNJ), on the primary human macrophage transcriptome. In uninfected macrophages as well as macrophages infected with dengue virus or treated with lipopolysaccharide to model bacterial sepsis, iminosugar treatment results in activation of the unfolded protein response and inhibition of several elements of the inflammatory response including signalling by the cytokines IFN-γ and TNF-α, and the inflammatory cascade mediated by NF-κB. Activation of the unfolded protein response as a result of treatment with MON-DNJ can be confirmed by analysis of phosphorylated (activated) NFE2L2, a transcription factor that functions principally to control oxidative stress in response to ER stress signals. Modulation of the inflammatory response of macrophages to dengue infection and bacterial sepsis is confirmed by analysis of secreted cytokines. As predicted by my transcriptomic experiments, levels of TNF-α and IFN-γ produced in response to dengue or lipopolysaccharide are reduced by treatment with MON-DNJ. Finally, I attempted to extend these observations to an animal model of dengue infection with a particular focus on TNF receptor and ligand superfamily members. Unfortunately, heterogeneity of cells types from tissue samples as well as limitations of the animal model complicate interpretation of these findings. Nevertheless, this thesis demonstrates that MON-DNJ is an effective dengue antiviral therapeutic and that this therapeutic activity may be related to both reduction of infectious virus as a consequence of inhibition of glycoprotein processing and as a result of changes to the host’s response to the pathogen. These results have been used in part to justify recently initiated clinical trials of MON-DNJ as a dengue antiviral therapy.

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Al, Matrood W. A. A. « Factors that enhance the ability of Pseudomonas aeruginosa to resist the action of antibiotics ». Thesis, Liverpool John Moores University, 2016. http://researchonline.ljmu.ac.uk/4727/.

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P.aeruginosa is one of the most important pathogens in nosocomial infections and fails to respond to standard treatment, particularly in the case of patients subjected to prolong antibiotic treatment. To generate a more comprehensive understanding of the failure of antimicrobial treatment, focusing especially on the adaptive resistance could be the key area that the bacterium develops in this phenomenon. Most studies on antibiotic resistance in P.aeruginosa have focused upon genotypic studies. This study set out to develop an in vitro model to examine the effect of continual exposure of P.aeruginosa PA01 to the antibiotics studied. Experiments were initially conducted to consider the factors that having a significant influence on antibiotic susceptibility using a novel fluorescence based assay (OxoPlate® system). P.aeruginosa was subjected to the action of tobramycin, amikacin and colistin under various environmental factors. The results of the in vitro analysis showed that, from among the three antibiotics used, amikacin was the antibiotic where resistance was most readily developed. From these results, chemostat studies were designed to examine prolonged exposure of the antibiotic to planktonic cells. Chemostat cultures were exposed to amikacin at sub-inhibitory concentrations using Evans defined synthetic medium at different dilution rates (D) under glucose limitation. Both cultures grown at 0.025h-1 and 0.06h-1 developed the following characteristics i. low-level amikacin resistance, which exhibited an increase in the MIC 4-fold. ii. a clear development of phenotypic resistance and this resistance was not acquired as evidenced by the loss of resistance on culture into fresh medium lacking antibiotic. iii. adaptive resistance to amikacin conferred low-level resistance to other aminoglycosides such as tobramycin and antibiotics with different modes of action such as colistin. Low oxygen availability was seen in the cultures grown at 0.099 h-1 and 0.125 h-1, which lead to i. the appearance of the so called “persister” phenotype. These persisters are sub populations of cells that showed a reduction in bacterial cell size as evidenced from the flow cytometry output as well as being slow growing and resistant ii. extracellular polymeric fibrils were produced in the cells derived after 72h incubation time. In all cases, continual exposure resulted in phenotypically distinct mucoid and non- mucoid colony morphotypes, which were clearly observed on amikacin-free nutrient agar. Some of these selected morphotypes showed from the MIC and MBC data a high-level resistance to the antibiotic when left without antibiotics. The biological responses resulting from these studies offer valuable clues underlying unsuccessful treatment. Conducting experiments using robust systems renders this project extremely novel in the field of microbiology and this will contribute to the development of viable treatment options and ultimately the reduction of the emergence of antibiotic resistance.

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Mubaraki, Murad. « Pharmacometabolomic study of the human malaria parasite, Plasmodium falciparum : new insights into parasite biology and mode of drug action ». Thesis, University of Liverpool, 2013. http://livrepository.liverpool.ac.uk/12337/.

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Malaria is a vector-borne parasitic disease spread by a bite of an infected female Anopheles mosquito that accounts for high morbidity and mortality, mainly in sub-Saharan Africa. Of the five species that can cause malaria in humans, Plasmodium falciparum is regarded the most virulent species. Antimalarial drugs, unaltered for many decades, remain the mainstay for treating P. falciparum infection. In addition, despite intensive research there remain significant knowledge gaps in understanding of the biology of the malaria parasite P. falciparum. These deficiencies hinder the ability of scientists to identify new targets for drug discovery at a time when new targets are urgently required, such as in the case of newly emerging drug resistant parasite strains. Therefore, an understanding of the biology of P. falciparum is helpful in identifying new drug targets. Metabolomics, defined as the comprehensive analysis of all metabolites in a biological system, offers a feasible platform for highly sensitive and specific analysis of the metabolic pathways of P. falciparum. This is supported by the assumption that metabolites are important players in biological systems and that resistant parasite strains may operate or alter single or multiple metabolic pathways in order to adapt to the drugs being used. Therefore, a targeted metabolomics approach was developed and validated (Chapter 3) in order to better understand the metabolic roles of mitochondria and the digestive vacuole of P. falciparum. Metabolite detection and quantification were conducted using a targeted LC-MS/MS metabolomics approach (Chapter 3). It was shown that metabolic activities, particularly carbohydrate metabolism, in trophozoite stage P. falciparum-infected RBC were remarkably higher than that of non-infected RBC (Chapter 4). This lead the study to progress further, examining the metabolic role of two components of the P. falciparum; the mitochondria and the digestive vacuole. A number of mitochondrial inhibitors selective for specific electron transport chain complexes and mitochondrial transporters were used to assess mitochondrial function in asexually growing trophozoite stage P. falciparum (Chapter 5 and 6). Despite the differing modes of action of the inhibitors, the metabolic fingerprints, which were carbamoyl-l-aspartate and dihydroorotate, from these experiments were consistent with the parasite mitochondrion playing a key role in pyrimidine biosynthesis at the point of dihydroorotate dehydrogenase (DHODH) (Chapter 5 and 6). This metabolic fingerprint, leading to parasite death, was quite distinct from fingerprints obtained from biologically distinct inhibitors such as heme-binding drugs (quinoline-containing antimalarials drugs) which primarily affected the metabolism of amino acids, perhaps in the digestive vacuole and parasite cytosol (Chapter 7). In contrast to genomic and proteomic approaches, metabolomics appears to better represent the parasites’ phenotype in response to drug perturbation. Pharmacometabolomics will therefore have significant utility in understanding the biological function of parasite components; and the mode of action, efficacy and toxicity of pharmaceutical drugs.

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Wong, Michael. « Rational design of small molecule probes for investigating the mechanism of action of the chemotherapeutic agents CDDO and artemisinin ». Thesis, University of Liverpool, 2015. http://livrepository.liverpool.ac.uk/2006368/.

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Adverse drug reactions (ADR) are a major concern for the pharmaceutical industry and health practitioners as they can cause morbidity and in severe cases mortality. ADRs are one of the major reasons why drugs fail during clinical trials so research directed at predicting ADRs to minimise failure is essential. The CDDO (2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oate) and the synthetic endoperoxide series are two promising classes that have potential for the treatment of cancers and malaria and may revolutionise treatment, within their fields, if approved for clinical use. The two main aims that are presented in this thesis are to; (i) design and synthesise novel analogues and chemical probes to identify potential molecular targets for both the CDDO and endoperoxide series (ii) develop appropriate in vitro test systems to help define the molecular mechanism of each class of drug. CDDO-Me (methyl 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oate) is one of the most potent inducers of Nrf2, a transcription factor that regulates the expression of numerous cell defence genes in mammalian cells. Nrf2 is sequestered in the cytosol by Keap1, which ‘senses’ chemical and oxidative stress via its 27 cysteine residues. Although CDDO-Me is one of the most potent inducers of Nrf2, the molecular target and chemical mechanism is still not defined. Current literature suggests that a reversible 1,4 conjugate addition to specific cysteine residue(s) located on the Keap1 protein results in an increase in Nrf2 levels. In order for SAR work to be performed a synthetic route to CDDO and analogues was developed which involved nine steps using oleanolic acid as starting material. Highlights of the chemistry included addition of the ketone using mCPBA and incorporation of the cyano group in steps 3 and 7 of the synthesis. In addition to preparing the target molecule CDDO a number of additional molecules were prepared to define the importance of functional groups in the A and C rings of CDDO. Genetically modified H4IIE rat hepatoma cells transiently transfected with the an Nrf2-sensitive luciferase reporter gene were used to screen the CDDO-Me analogues, including DDO-Me which lacks a cyano group on the A ring, for their ability to induce Nrf2. NMR studies with model thiols were performed to determine the ability of these compounds to form reversible or non-reversible adducts. Mass spectrometry (MS) was used to confirm the NMR data and interpretations. In total, four probes were identified that reacted in a non-reversible fashion: DDO-Me, DDO-Al and DDO-Az (click probe versions of the parent DDO-Me that can be used to facilitate proteomic studies) and CDDO-Epox (a probe with similar overall structure to CDDO-Me but can react at the β-carbon in a non-reversible fashion; this feature should aid proteomic approaches to reactive cysteine residue identification). To further investigate if these compounds were reactive to cysteine residues within a model protein, recombinant human GSTP1 was used as a model protein for chemically reactive molecules. Cys-47 located on GSTP1 has been shown to react with other electrophones and during our studies LCMS has confirmed that all four of the synthesised active probes were capable of attaching covalently to Cys-47 of GSTP1. The emergence of malaria parasite resistance to most available drugs, including the semi-synthetic artemisinin derivatives artemether and artesunate, has led to efforts to create new synthetic peroxides as potential antimalarial agents. Leading examples of synthetic endoperoxides include OZ277 (arterolane), a molecule in phase III clinical trials in combination with piperaquine, and OZ439, a second generation derivative with improved pharmacokinetics and enhanced in vivo antimalarial activity. 1,2,4,5-Tetraoxanes are another class of endoperoxide with proven excellent antimalarial profiles against both chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum and oral activity in murine models of the disease. It is currently widely accepted that endoperoxides have a similar antimalarial mechanism to artemisinin, whereby Fe2+ medicated generation of cytotoxic carbon-centred radicals, results in death of the parasite. It is presumed that C-radicals can react with important key proteins; however, the specific molecular target(s) that leads to eventual parasite death are still unknown. A chemical synthesis of tetraoxane probes that contain a UV chromophore was performed and analogues were subsequently screened for antimalarial activity. The most active tetraoxane identified was exposed to a range of Fe2+ salts and conditions developed to mimic the biological environment. Primary, secondary and novel carbon-centred radical derived products (surrogate markers of bioactivation) were purified using UV-HPLC, characterised and submitted as chemical probes and standards for biological studies. In order for proteomic studies to be initiated, an allyl or azide group was incorporated into a semi-synthetic artemisinin skeleton. The azide (and alkyne) functional group within these probes provides a handle for protein pull down via click chemistry. Azide and acetylenes were chosen over direct linkage to the biotin group to reduce steric hindrance in the semi-synthetic probe. The synthesised click probes were tested for antimalarial activity and were submitted for protein pull down and identification of potential molecular targets. Similarly DDO allyl and azide were synthesised and were tested for Nrf2 induction and further confirmed as viable probes via NMR experiments with simple thiols and GSTP1. In summary, novel CDDO non reversible probes were synthesised and have shown potential as chemical tools to identify the molecular targets/mechanisms by which these compounds activate Nrf2. Tetraoxanes also have been prepared along with artemisinin click probes and the latter have been submitted for click chemistry pull down experiments, within Plasmodium falciparum parasites, to identify potential molecular targets.

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Hughes, George Marc. « Design and mechanism of action of novel organoiridium(iii) azopyridine anticancer complexes ». Thesis, University of Warwick, 2018. http://wrap.warwick.ac.uk/103913/.

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This thesis is concerned with the synthesis, characterisation, and purification of 19 organoiridium(III) complexes, seventeen of which are novel. The complexes are of the general structure [CpX Ir(azopyridine)Z]A, where the iridium centre is coordinated to either a pentamethyl-cyclopentadienyl (Cp*) ligand, a tetramethyl(phenyl)-cyclopentadienyl Cpxph ligand, or a tetramethyl(biphenyl)-cyclopentadienyl Cpxbiph ligand. The azopyridine acts as an N,N-chelated bidentate ligand with a variety of substituents, the chemical and biological e↵ects of which are investigated. Z represents a monodentate halido ligand. In this work, complexes with chlorido and iodido ligands in this position are investigated. A represents the counterion to the cationic organoiridium complex. In this work, complexes bearing the hexafluorophosphate (PF6 ), Cl , and I anions are investigated. X-ray crystal structures of eight of the complexes are determined, confirming that the complexes adopt the expected ’piano-stool’ configuration. The anticancer properties of these complexes are thoroughly investigated in multiple cancer cell lines, revealing that several are more potent than many clinically-utilised chemotherapeutics including cisplatin (CDDP), as well as many previously reported metal-based anticancer complexes. The mechanism of action (MoA) of this family of complexes has been investigated, revealing an MoA based on the generation of reactive oxygen species (ROS) and superoxide (SO) in addition to mitochondrial membrane depolarisation. Drugs with this MoA hold the potential to selectively kill cancer cells over normal ones as cancer cells have higher levels of basal ROS and are therefore more sensitive to perturbation of their ROS balance. The charge, solubility, hydrophobicity, hydrolytic behaviour, and mechanism of action (MoA) of these complexes can all be modified with small synthetically trivial adjustments, resulting in highly potent complexes. This demonstrates this family of complexes as an effective and versatile platform for drug design.

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Schroeder, Frederick Albert. « A Role for Histone Modification in the Mechanism of Action of Antidepressant and Stimulant Drugs : a Dissertation ». eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/370.

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Depression and stimulant drug addiction each result in massive losses of health, productivity and human lives every year. Despite decades of research, current treatment regimes for depression are ineffective in approximately half of all patients. Therapy available to stimulant drug addicts is largely ineffective and moreover, dedicated treatments for drug dependence (including abuse of cocaine) are non-existent. Thus, there is a pressing need to further understanding of the molecular mechanisms underlying these disorders in order to develop novel, targeted therapeutic strategies. Chromatin remodeling, including changes in histone acetylation, has been proposed to play a role in both the etiology and treatment of depression and stimulant abuse. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate numerous cellular processes, including transcription, cell cycle progression and differentiation. Moreover, histone acetylation has been shown to regulate hippocampal neurogenesis, a cellular response associated with the pathogenesis and treatment of depression and stimulant abuse (Hsieh et al., 2004, Yamaguchi et al., 2004, Fischer et al., 2007). Ultimately, such basic cellular processes impact higher order function, namely cognition and emotion. Indeed, recent studies suggest that HDAC activity in selected forebrain regions, including ventral striatum and hippocampus, modulate stimulant- and antidepressantinduced behavior (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). These reports highlight an association between chromatin remodeling and diverse behavioral changes, including changes induced by the pleiotropic HDAC inhibitor, sodium butyrate (SB), (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). However, behavioral, brain-metabolic and molecular effects of SB treatment in the context of rodent models of depression, dopaminergic sensitization and repeated cocaine administration remained unclear. The work described in this thesis illustrates the potential for chromatin modifying drugs in mechanisms underlying the experimental pharmacology of depression and stimulant addiction. Specifically, the data presented here support the view that treatment with the short chain fatty acid, sodium butyrate enhances: (1) antidepressant-like behavioral effects of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (2) locomotor sensitization induced by repeated administration of the dopamine D1/D5 receptor agonist SKF82958; and(3) brain metabolic activation upon repeated cocaine administration as evidenced by fMRI in awake rats. Furthermore, this report provides evidence that these treatment paradigms will result in chromatin modification changes associated with active transcription, in addition to increased mRNA levels of plasticity-associated genes, including brain-derived neurotrophic factor (BDNF) at key brain regions implicated in the pathogenesis of depression and stimulant addiction. To date, little is known regarding the underlying mechanisms of action mediating the enhancing effects of sodium butyrate on the various antidepressant- and stimulantrelated paradigms. Our findings underscore the potential of chromatin-modifying drugs to profoundly affect the behavioral response of an animal to antidepressant and stimulant drugs and warrants consideration in the context of developing novel therapeutic strategies.

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Courtney, Hamish. « Determinants of insulin action : physiological and therapeutic implications ». Thesis, Queen's University Belfast, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343100.

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Buckshey, Sakshi. « Remineralizing action of CPP-ACP reagents on artificial carious lesions ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46848915.

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Makhani, Kiran, et Kiran Makhani. « Mechanism of Action of ERBB Decoy Cancer Therapeutic Peptide SAH5 ». Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/626139.

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Breast cancer is the most prevalent type of cancer and second leading cause of death in women. Among others, the triple negative breast cancer (TNBC) is the most invasive as it has the highest recurrence and death rates with no targeted therapeutic available thus far. Epidermal Growth Factor Receptor (EGFR) is one of the important targets as more than fifty percent of the TNBC overexpress it but all the therapies designed against it have failed to show significant results. The juxtamembrane domain of EGFR has been explored comparatively recently and has been used to design a decoy peptide with the anticipation to affect the EGFR downstream functions. Previous research has shown it to cause cell death in cancer cells. This study is aimed towards deciphering the mechanism of action of the stapled form of this decoy peptide-SAH5. It presents evidence that the peptide leads to an immediate intracellular calcium release from the Inositol 1,4,5 triphosphate on the endoplasmic reticulum, an inhibition of which can rescue SAH5 induced cell death. The study also demonstrate that the peptide is able to increase the production of Reactive Oxygen Species (ROS) in mitochondria, part of which is triggered by the peptide-induced calcium release.

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Waters, Cerith. « Acceptance and commitment therapy : efficacy and mechanisms of therapeutic action ». Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/37760/.

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The individual, organisational and societal impact of psychological distress among working populations is well established. Recently, Acceptance and Commitment Therapy (ACT) has been identified as a promising approach for improving the psychological wellbeing of distressed employees. Nonetheless, few studies have examined the efficacy of ACT in the occupational context and even fewer studies have conducted comprehensive tests of the mechanisms of therapeutic action in ACT. The current research examined the efficacy of a one day ACT intervention that was delivered to NHS employees experiencing psychological distress. A key focus of this research was an examination of the mechanisms of therapeutic action in ACT. In study one, a non-randomised controlled design was used with 17 participants assigned to the ACT intervention and 18 participants assigned to a waiting list. A two-week and three-month follow-up period was used in this study. Participants originally assigned to the waiting list went on to receive the intervention after the three month follow-up and were again assessed at two-weeks and three-months post-treatment. In study two, six of the participants were interviewed about their views on the aspects of the ACT intervention that promoted psychological changes and their responses were analysed thematically. Compared to the control group, participants who received the intervention displayed statistically significant reductions in the severity of psychological distress at two-weeks and three-months post-treatment. Importantly, the majority of participants displayed clinically significant change at both assessments. In line with ACT’s theoretical underpinnings, the intervention significantly increased participants’ psychological flexibility and mindfulness skills and decreased cognitive fusion. However, in a multiple-mediator statistical analysis, improvements in psychological distress were only mediated by improvements in psychological flexibility. The themes generated from the thematic analysis converge with the quantitative data—resembling closely the construct of psychological flexibility. Limitations of the study and implications for future research are discussed.

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Spandler, Helen. « Asylum to action : Paddington Day Hospital, therapeutic communities and beyond ». Thesis, Manchester Metropolitan University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247203.

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Al-Zobaidy, Mohammed. « Differential actions of methlyarginines in the rat aorta ». Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3838/.

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The PhD project is about the Regulation of vascular tone by endothelium. It involves studying the effects of methylated arginine analogues such as monomethyl arginine (L-NMMA) and asymmetric dimethylarginine (ADMA) on nitric oxide (NO) activity in rat aorta using organ baths containing Krebs solution at 37 ˚C and gassed with 95% O2 and 5% CO2. These two inhibitors of endothelial nitric oxide synthase enzyme (eNOS) showed an anomalous action, as they inhibited basal NO activity (assessed by enhancement of phenylephrine-induced tone and by blocking relaxations produced by superoxide dismutase or the PDE5 inhibitor; T0156) but not that is stimulated by agonists like acetylcholine or the calcium ionophore A23187. After establishing these findings I will try to find the reason(s) for these paradoxical actions of these two endogenously synthesized inhibitors of eNOS.

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Lilliengren, Peter. « Exploring therapeutic action in psychoanalytic psychotherapy : Attachment to therapist and change ». Doctoral thesis, Stockholms universitet, Psykologiska institutionen, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-106501.

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The overall aim of this thesis was to explore therapeutic action in psychoanalytic psychotherapy from different perspectives (patient, therapist, observer), using different methodological approaches (qualitative and quantitative). Study I explores patients’ views of therapeutic action with grounded theory methodology. The results indicated that talking openly in a safe therapeutic relationship led to new relational experiences and expanding self-awareness. Hindering factors included difficulties “opening up” and experiencing something missing in treatment. Study II investigates experienced therapists’ views of therapeutic action. The development of a close and trusting relationship was perceived as the core curative factor. Patients’ fear of closeness hindered treatment from the therapists’ perspective. Study III involves the development and psychometric examination of a new rating scale for patient-therapist attachment (Patient Attachment to Therapist Rating Scale; PAT-RS). Inter-rater reliability was good for three of the subscales (Security, Deactivation, Disorganization), but poor for one (Hyperactivation). Patterns of correlations with other measures suggest construct validity for the reliable subscales. Study IV examines the relationships between secure attachment to therapist, alliance, and outcome. Linear mixed-effects models, controlling for therapist effects, treatment length and patient-rated alliance, indicated that secure attachment to therapist relates to outcome. Further, the unique variance associated with secure attachment to therapist predicted continued gains in functioning during follow-up. The results of this thesis suggest that the development of a secure attachment to the therapist is a central mechanism of therapeutic change. The results are discussed in relation to established notions of therapeutic action in psychoanalytic psychotherapy. Two tentative process models that may be useful for clinical practice and future research are proposed.

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Epub ahead of print.

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Smith, Andrew Mark. « The action of therapeutic antibodies of varying geometry on lymphoma cells ». Thesis, University of Winchester, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550213.

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Lessard, Sarah, et not supplied. « Therapeutic interventions for lipidinduced insulin resistance in skeletal muscle : mechanisms of action ». RMIT University. Medical Sciences, 2006. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20070205.101938.

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It has long been known that in addition to disruptions in glucose homeostasis, individuals with insulin resistance have a breakdown in lipid dynamics, often manifested by elevated levels of circulating fatty acids (FA) together with accumulation of lipids in insulin-sensitive tissues, including skeletal muscle. However, little is known about how common therapies used to treat insulin resistant individuals (such as Rosiglitazone and exercise training) improve skeletal muscle lipid and glucose metabolism. Thus, the primary aim of the studies undertaken for this thesis was to enhance our understanding of the mechanisms by which Rosiglitazone and exercise training improve skeletal muscle lipid metabolism and insulin sensitivity in two distinct models of insulin resistance. The first investigation determined the effect of chronic Rosiglitazone treatment on the accumulation of lipid metabolites and enzymatic regulators of lipid metabolism in the skeletal muscle of obese Zucker rats. The observation that Rosiglitazone treatment exacerbated the accumulation of muscle ceramide and diacylglycerol in skeletal muscle, while improving glucose tolerance led to the conclusion that this insulin sensitising drug improves insulin sensitivity by mechanisms other than reduction of fatty acid metabolites in this tissue. Accordingly, the second investigation sought to identify an alternative mechanism by which Rosiglitazone treatment may improve skeletal muscle insulin sensitivity. It was found that Rosiglitazone restored AMP-activated protein kinase (AMPK) á2 activity in the skeletal muscle of obese Zucker rats, providing a potential peroxisome proliferator activated receptor (PPAR) ã-independent mechanism by which this drug may mediate its insulinsensitising actions. The final experiment undertaken for this thesis determined the independent and interactive effects on Rosiglitazone and exercise training on various aspects of skeletal muscle glucose and lipid metabolism in a model of diet-induced insulin resistance, the high-fat fed rat. Exercise training, but not Rosiglitazone treatment restored skeletal muscle insulin sensitivity in high-fat fed rats. Improvements in insulin sensitivity with exercise training were associated with increased FA oxidation, increased AMPK activity and a normalisation of the expression of the Akt substrate, AS160. In contrast, Rosiglitazone treatment was associated with increased FA uptake and decreased insulin-stimulated glucose uptake in skeletal muscle. Exercise prevented the accumulation of skeletal muscle lipids in Rosiglitazone-treated animals when the two treatments were combined. In summary, the results from the studies undertaken for this thesis provide novel information regarding the mechanisms by which two insulinsensitising therapies, exercise training and Rosiglitazone treatment, act to improve glucose and lipid metabolism in skeletal muscle.It has long been known that in addition to disruptions in glucose homeostasis, individuals with insulin resistance have a breakdown in lipid dynamics, often manifested by elevated levels of circulating fatty acids (FA) together with accumulation of lipids in insulin-sensitive tissues, including skeletal muscle. However, little is known about how common therapies used to treat insulin resistant individuals (such as Rosiglitazone and exercise training) improve skeletal muscle lipid and glucose metabolism. Thus, the primary aim of the studies undertaken for this thesis was to enhance our understanding of the mechanisms by which Rosiglitazone and exercise training improve skeletal muscle lipid metabolism and insulin sensitivity in two distinct models of insulin resistance. The first investigation determined the effect of chronic Rosiglitazone treatment on the accumulation of lipid metabolites and enzymatic regulators of lipid metabolism in the skeletal muscle of obese Zucker rats. The observation that Rosiglitazone treatment exacerbated the accumulation of muscle ceramide and diacylglycerol in skeletal muscle, while improving glucose tolerance led to the conclusion that this insulin sensitising drug improves insulin sensitivity by mechanisms other than reduction of fatty acid metabolites in this tissue. Accordingly, the second investigation sought to identify an alternative mechanism by which Rosiglitazone treatment may improve skeletal muscle insulin sensitivity. It was found that Rosiglitazone restored AMP-activated protein kinase (AMPK) á2 activity in the skeletal muscle of obese Zucker rats, providing a potential peroxisome proliferator activated receptor (PPAR) ã-independent mechanism by which this drug may mediate its insulinsensitising actions. The final experiment undertaken for this thesis determined the independent and interactive effects on Rosiglitazone and exercise training on various aspects of skeletal muscle glucose and lipid metabolism in a model of diet-induced insulin resistance, the high-fat fed rat. Exercise training, but not Rosiglitazone treatment restored skeletal muscle insulin sensitivity in high-fat fed rats. Improvements in insulin sensitivity with exercise training were associated with increased FA oxidation, increased AMPK activity and a normalisation of the expression of the Akt substrate, AS160. In contrast, Rosiglitazone treatment was associated with increased FA uptake and decreased insulin-stimulated glucose uptake in skeletal muscle. Exercise prevented the accumulation of skeletal muscle lipids in Rosiglitazone-treated animals when the two treatments were combined. In summary, the results from the studies undertaken for this thesis provide novel information regarding the mechanisms by which two insulinsensitising therapies, exercise training and Rosiglitazone treatment, act to improve glucose and lipid metabolism in skeletal muscle.

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Scott, Brigitte Clare. « Analysis of the antioxidant action of potential food antioxidants and therapeutic agents ». Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338445.

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Bates, Sarah H. « Investigation of potential intervention targets to improve insulin action : a therapeutic approach ». Thesis, Aston University, 1999. http://publications.aston.ac.uk/10980/.

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Impaired insulin action (insulin resistance) is a key factor in the pathogenesis of diabetes mellitus. To investigate therapeutic targets against insulin resistance, this thesis explores the mechanism of action of pharmacological agents and exogenous peptides known or suspected to modify insulin action. These included leptin, a hormone primarily involved in the regulation of body weight; sibutramine, an antiobesity agent; plant-derived compounds (pinitol and chamaemeloside) and agents known to affect insulin sensitivity, e.g. metformin, tolbutamide, thiazolidinediones, vanadyl sulphate and thioctic acid. Models used for investigation included the L6 skeletal muscle cell line and isolated skeletal muscles. In vivo studies were undertaken to investigate glycaemia, insulinaemia, satiety and body weight in streptozotocin-induced diabetic mice and obese (ob/ob) mice. Leptin acutely altered insulin action in skeletal muscle cells via the short form of the leptin receptor. This direct action of leptin was mediated via a pathway involving PI 3-kinase but not Jak2. The active metabolites of sibutramine had antidiabetic properties in vivo and directly improved insulin sensitivity in vitro. This effect appeared to be conducted via a non-PI 3-kinase-mediated increase in protein synthesis with facilitated glucose transport, and was independent of the serotonin and noradrenaline reuptake inhibition produced by sibutramine. Pinitol (a methyl inositol) had an insulin mimetic effect and was an effective glucose-lowering agent in insulinopenic states, acting directly on skeletal muscle. Conversely chamaemeloside appeared to improve glucose tolerance without directly altering glucose transport. Metformin directly increased basal glucose uptake independently of PI 3-kinase, possibly via an increase in the intrinsic activity of glucose transporters. Neither tolbutamide nor thiazolidinediones directly altered insulin sensitivity in L6 skeletal muscle cells: however vanadyl sulphate and thioctic acid increased glucose transport but appeared to exert toxic effects at therapeutic concentrations. Examination of glucose transport in skeletal muscle in this thesis has identified various components of post-receptor insulin signalling pathways which may be targeted to ameliorate insulin resistance.

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Milton, Lateshia B. « Engaging Parents of Black Students in Therapeutic Processes to Decrease Disciplinary Action ». ScholarWorks, 2019. https://scholarworks.waldenu.edu/dissertations/7491.

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The disproportionate frequency of disciplinary actions involving Black students in the school setting is of concern. The behavior that leads to disciplinary action may be related to adverse childhood events that resulted in behavior related to trauma. This action research study focused on how school social workers in 1 school district might engage parents of Black students in the therapeutic processes to decrease disciplinary action. In this study, the trauma systems therapy (TST) model was presented to a focus group composed of school social workers who served Black students. The social workers were asked to share their thoughts in response to 5 questions related to how social workers might engage parents of Black students in the therapeutic processes to decrease disciplinary action. Data analysis included reviewing the focus-group transcript and coding categories. Themes in the responses to each question were categorized to provide insight into the feasibility of implementing TST in practice with Black students who received disciplinary action. The results of this research might inform school social workers' practice by helping them connect adverse childhood experiences and disciplinary outcomes as they engage parents of Black students in the therapeutic process to decrease disciplinary actions. The implications of this study for positive social change include modifying school social work services, creating safe therapeutic school environments, and changing the course of disciplinary actions for Black students.

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Cholisoh, Zakky. « Viral infection in a murine model of allergic airways inflammation : actions of corticosteroids ». Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/58454/.

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Viral respiratory infection exacerbates asthma symptoms in almost all patients with allergic asthma. Asthma symptoms in viral associated asthma exacerbation are often severe and require urgent care as well as hospitalisation. Corticosteroids are the mainstay treatment for asthma. However, they are less effective in treating virus associated asthma exacerbation. The main aim of the thesis is to determine the role of virus infection in airway allergic inflammation and then define the effects of corticosteroids in virus associated exacerbations of airway allergic inflammation. Mice sensitised and challenged with ovalbumin demonstrated most of the main features of asthma including lung cellular inflammation with eosinophilia, early phase asthmatic responses (EAR), late phase asthmatic responses (LAR), and airway hyperresponsiveness (AHR) to methacholine provocations. Treatment with either systemic (dexamethasone: DEX) or inhaled (fluticasone propionate: FP) corticosteroids in the murine ovalbumin allergic airways inflammation model attenuated inflammatory cells influx and eosinophilia, LAR, and the AHR. Influenza A (H1N1/PR8) is the most infective to mice compared to human parainfluenza virus type 3 (HPIV3), and a synthetic dsRNA, poly (I:C). Influenza infection in mice caused a significant increase of inflammatory cell influx in the airways with marked neutrophilia, and AHR. Ovalbumin challenge in the acute course of influenza infection on a murine model of allergic airways inflammation exacerbated the inflammatory cells influx, LAR, and AHR. Treatment with either DEX or FP attenuated the airway cellular inflammation, LAR, but not the AHR. Mice only infected with influenza were resistant to the corticosteroids (DEX and FP) treatment. DEX but not FP showed antiviral activity against HPIV3 and influenza A in vitro. These data suggest that influenza infection in a murine model of allergic airways inflammation exacerbates the inflammation and alters the sensitivity toward corticosteroids. It is also suggested that some elements in the influenza associated exacerbation of murine model of allergic airways inflammation are refractory or not regulated by corticosteroid treatment.

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Moss, Joe. « Anti-inflammatory actions of nutraceuticals : novel emerging therapies for atherosclerosis ? » Thesis, Cardiff University, 2018. http://orca.cf.ac.uk/111849/.

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Background Cardiovascular disease (CVD)-related events such as myocardial infarction and stroke remain the world’s leading cause of death. The incidence of CVD-related events is expected to rise in the future due to the increase in the global prevalence of obesity and diabetes, in addition to less economically developed countries adopting a western style diet. Atherosclerosis is a chronic inflammatory disease which is the underlying cause of CVD and characterised by the build-up of fatty deposits within the walls of medium and large arteries. Macrophages play critical roles during the pathogenesis of atherosclerosis, including the uptake of modified low-density lipoproteins to form foam cells. CardioWise is a dietary supplement developed by Cultech Limited which contains the anti-inflammatory compounds ω-3 PUFAs, flavanols and phytosterols. The aim of this project was to assess the cardiovascular protective effects of CardioWise and its individual components in isolation using in vitro and in vivo model systems. Results Foam cell formation was attenuated in human THP-1 macrophages treated with CardioWise. In addition, CardioWise reduced pro-inflammatory gene expression, monocyte recruitment and M1 macrophage phenotype polarisation. CardioWise was also found to increase HDL cholesterol levels and attenuate circulating levels of pro-inflammatory cytokines in wild type mice. Further investigation identified (+)-catechin within CardioWise as a key beneficial molecule to explore in greater detail. In vitro experiments demonstrated that catechin reduced monocyte migration and reactive oxygen species generation. Wild type mice treated with catechin were also found to receive anti-atherogenic benefits such as increased HDL cholesterol levels and reduced pro-inflammatory cytokine levels. Conclusion The findings of this study show that CardioWise and catechin are capable of exerting strong anti-inflammatory effects on several stages of atherosclerosis disease development in vitro. Furthermore initial in vivo studies using wild type mice revealed that both treatments are also capable of exerting several cardiovascular protective effects. Reasons for these beneficial effects have been proposed in this thesis and future studies outlined.

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Steketee, Pieter Christiaan. « Investigating the mode of action of AN5568, a novel therapeutic against African trypanosomiasis ». Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7478/.

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The protozoan parasite Trypanosoma brucei is the causative agent of Human African Trypanosomiasis (HAT) and Nagana disease in mammals. These diseases present a major socioeconomic burden to large areas of sub-Saharan Africa. Current therapeutics involve complex and toxic regimens which can lead to fatal side-effects. In addition, there is evidence for drug resistance emerging in the field. Hence, there is a desperate need for novel therapies. Benzoxaboroles are a novel class of boron-containing compounds under development for use against a wide spectrum of diseases. AN5568 is a lead compound for the treatment of HAT, which has demonstrated effective clearance of both early- and late-stage trypanosomiasis in a murine model, and is currently undergoing clinical trials. However, the mechanism by which AN5568 kills T. brucei is elusive. In this study we sought to use 'omics'-based techniques to investigate the mode of action of AN5568 in a laboratory strain of Trypanosoma brucei brucei. Cells treated with the benzoxaborole showed significant perturbations in methionine metabolism. In particular, there were increases in S-adenosyl-L-methionine, an essential methyl group donor involved in methyltransferase reactions. These changes were similar to those elicited by the nonspecific methyltransferase inhibitor sinefungin. Changes were also observed in lipid metabolism, sugar nucleotide metabolism and glycophosphatidylinositol biosynthesis. Further analyses were carried out to investigate the effect of AN5568 on cellular stress responses and cell morphology. To further probe the mechanics of AN5568-treatment, a drug-resistant cell line was generated. This cell line showed cross-resistance with sinefungin, further supporting similar modes of action for these two drugs. Interestingly, the AN5568-resistant cell line exhibited upregulation of procyclic form-specific genes, as well as downregulation of blood-stream form-specific genes, which led to the hypothesis that the cell line had undergone a differentiation event. However, microscopy analysis showed that overall morphology of the cells still resembled those of bloodstream forms, despite them having acquired a procyclic-like metabolic physiology. A secondary aim of this project was to elucidate the metabolic changes that lead to increased growth rates in T. brucei cells undergoing loss-of-heterozygosity on chromosome 10. This phenomenon, whereby a significant portion of the chromosome is lost, has been observed independently on multiple occasions in lab adapted T. brucei strains, yet how this alteration affects intracellular metabolism was hitherto unknown. Using two procyclic T. brucei cell lines, this study was able to show that the increased growth rates are glucose-dependent with a potential intracellular alteration in succinate and acetate production. These data have important implications for the field, where LOH has been observed in the clonally expanding T.b. gambiense type I.

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Woods, Margaret Annaliese. « Molecular mechanisms of action of therapeutic monoclonal antibodies on T lymphocytes in vitro ». Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627301.

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Mykytyuk, O. P. « Therapeutic hypothermia in intensive cardiology : definition, mechanisms of action, safety and technical aspects ». Thesis, БДМУ, 2020. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18054.

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RODER, EMANUELA. « The complexity of therapeutic action in DBT : preliminary studies on process and outcome ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241311.

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La Dialectical Behavior Therapy (DBT) è un programma di trattamento cognitivo-comportamentale strutturato, complesso e ricco, messo a punto per pazienti con Disturbo Borderline di Personalità (BPD) e gravi comportamenti disfunzionali (tentativi suicidari, autolesività, instabilità relazionale, comportamenti impulsivi). DBT ha dimostrato la sua efficacia in numerosi studi: i tentativi suicidari e i comportamenti disfunzionali si sono ridotti, mentre la regolazione emotiva e il funzionamento generale dei pazienti sono migliorati. La ricerca presentata i prefigge di valutare l’efficacia e i meccanismi d’azione di DBT, esaminando sia la dimensione di outcome, sia la dimensione di processo. La prima parte dell’elaborato è dedicata alla presentazione del modello DBT. Se ne discutono i fondamenti teorici, gli accordi alla base del trattamento, le modalità del programma terapeutico e le strategie di intervento. La seconda parte dell’elaborato è una valutazione dell’efficacia di DBT, rispetto alle variabili target. Lo studio è di tipo longitudinale ed è stato condotto seguendo le linee guida internazionali. DBT è stata messa a confronto con un programma di trattamento comparabile per tipologia di pazienti, obiettivi e complessità. Il campione è composto da 95 pazienti ambulatoriali, valutati ogni tre mesi. Poiché ci si attendeva che il contributo della variabilità individuale fosse rilevante, sono stati utilizzati modelli lineari gerarchici con effetti casuali. I risultati hanno mostrato che i tentativi suicidari, i comportamenti autolesivi, la disregolazione emotiva e comportamentale sono diminuiti in entrambi i gruppi dopo un anno; i modelli hanno mostrato come i soggetti differissero nella quota di cambiamento. Inoltre, i risultati sul campione dei completer hanno suggerito che il setting di gruppo e l’intensità del trattamento potrebbero agire quali specifici meccanismi terapeutici. La terza parte dell’elaborato si compone di una serie di studi di processo con un disegno single case, inseriti nel filone della ricerca process-outcome: si tratta della valutazione di due coppie terapeutiche, una con esito favorevole ed una con esito parziale. Le pazienti erano due giovani donne con diagnosi di BPD, differenti per profilo di personalità e comportamenti disfunzionali; hanno seguito un programma DBT standard con il medesimo terapeuta, un clinico esperto. Sono state esaminate le sedute durante il primo anno di trattamento. Si sono considerate tanto la dimensione tecnica quanto quella relazionale del processo terapeutico, esaminando entrambe da una prospettiva macroanalitica e microanalitica. I risultati hanno mostrato come alcuni aspetti siano riscontrabili in ambedue le coppie terapeutiche: l’aderenza al modello di trattamento e l’atteggiamento del terapeuta orientato alla collaborazione. D’altra parte, sono emerse specificità relative alle coppie terapeutiche. Nel trattamento della paziente con esito positivo, è presente un clima relazionale globalmente positivo, terapeuta e paziente riescono ad affrontare in modo proficuo anche le incomprensioni. Invece, nel trattamento della paziente con esito parziale, terapeuta e paziente faticano a trovare una sintonizzazione e a lavorare in modo sinergico, rimanendo bloccati in dinamiche problematiche e senza riuscire a conseguire pienamente gli obiettivi prefissati. Nel loro insieme, i risultati hanno confermato l’efficacia e la complessità di DBT. Più precisamente, hanno messo in luce le sovrapposizioni e le differenze tra DBT e altri modelli teorici, in particolare con gli interventi che promuovono il funzionamento riflessivo. Inoltre, i risultati hanno confermato l’importanza di una relazione collaborativa tra terapeuta e paziente. In sintesi, è possibile concludere che i meccanismi dell’azione terapeutica in DBT possono essere compresi solo alla luce delle dinamiche del processo terapeutico entro cui si verificano.
Dialectical Behavior Therapy (DBT; Linehan, 1993, 2014) is a structured, complex and comprehensive cognitive-behavioral treatment program for patients with Borderline Personality Disorder (BPD) and severe dysfunctional behaviors (repeated suicidal attempts, self-harm behaviors, relational instability, other impulsive behaviors). Up to now, DBT proved its effectiveness in several studies: suicide attempts and dysfunctional behaviors decreased, while emotional regulation and general functioning improved. The present research aimed at assessing the effectiveness of DBT and its mechanisms of action, evaluating both outcome and process dimensions. The first part of the thesis is dedicated to the presentation of the DBT model, examining its theoretical foundations, the agreements underlying the treatment, the modalities of therapeutic program, and the strategies of intervention. The second part of the thesis is an evaluation of the effectiveness of DBT, examining the course over time of the target variables. The study is longitudinal, single-blind, with a two-arm parallel design, conducted following the international guidelines for the outcome studies on intention-to-treat samples. DBT was compared with another treatment program comparable by patient type, objectives, and complexity of interventions. The sample was comprised by 95 outpatients, assigned to groups with the minimisation procedure and assessed every three months. Since the individual variability was expected to be consistent, Hierarchical Linear Models with random effects were used. Results showed that suicidality, self-harm, emotional and behavioral dysregulation decreased in both groups after one year; unconditional growth models indicated that subjects differed in the elevation and in the rate of change. Moreover, results on the completers’ subsample suggested that the group setting and the intensity of treatment could represent specific therapeutic mechanisms. The third part of the thesis is composed by process studies with a single-case design, in the strand of the process-outcome research: the empirical evaluation of two therapeutic couples, one with a favorable outcome and one with a partial outcome, was conducted. The patients were two young women with a diagnosis of Borderline Personality Disorder, different for personality profile and dysfunctional behaviors at the beginning of treatment; they followed a DBT standard program with the same therapist, a male experienced clinician. Sessions over the first year of treatment were examined (N1 = 38; N2 = 37). The technical and the relational dimensions of the therapeutic process were assessed and examined through a macroanalytic and microanalytic perspective. Results showed that some aspects are present in both couples: namely, the adherence to the treatment model and the attitude of the therapist oriented towards collaboration. On the other hand, specificities relating to each therapeutic couple emerged. In the treatment of the patient with positive outcomes, there was a globally positive relational climate; furthermore, therapist and patient can deal even with episodes of misunderstanding. Instead, in the treatment of the patient with partial outcomes, therapist and patient struggled to find an attunement and to work in synergy, remaining trapped in problematic relational patterns and without fully achieving the therapeutic objectives previously agreed. Taken together, results confirmed the effectiveness and the complexity of DBT. More specifically, they shed light on overlaps and differences between DBT and other theoretical models, in particular interventions promoting reflective functioning. Furthermore, the importance of a collaborative relationship between therapist and patient was confirmed. Overall, results suggested that mechanisms of action in DBT can be understood only in light of the dynamics of the therapeutic process in which they occur.

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He, Lin. « Defining the role of the actin cytoskeleton in cellular uptake of cell penetrating peptides ». Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/94910/.

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The increased need for macromolecular therapeutics, such as proteins and nucleotides, to reach intracellular targets asks for more effective delivery vectors and a higher level of understanding of their mechanism of action. Cell Penetrating Peptides (CPPs) have been shown to deliver a range of macromolecules into cells either through direct plasma membrane translocation or by endocytosis. All known endocytic pathways involve cellcortex remodelling, a process shown to be regulated by reorganisation of the actin cytoskeleton. Links between actin remodelling and CPP uptake has been shown but more information is required to determine the extent of this association and how it could influence further research into improving the delivery capacity of these entities. This project, by using the CPP octaarginine (R8) investigated how actin disorganisation influences the cellular entry of this peptide when attached to a model fluorophore Alexa 488 or Enhanced Green Fluorescent Protein (EGFP). A confocal microscopy technique was initially developed, allowing for high-resolution and spatial characterization of the actin cytoskeleton at different cell depths. Analysis using this developed method was used to highlight that serum starvation has a strong influence on the capacity of R8 to cause membrane blebs and possibly macropinocytosis. Using a range of direct or indirect actin inhibitors this work also highlighted how they can rapidly cause dramatic cellular deformities beyond the level of actin or more subtly affect actin organisation. Further confocal studies revealed that choice of cell line significantly affects the effect of actin disruption on CPP entry and that this is highly dependent on the nature of the probe. This was exemplified by results showing inhibition of EGFP-R8 uptake in HeLa cells treated with cytochalasin D, ! ! ii! latrunculin B and jasplakinolide but a dramatic increase in uptake in A431 cells when they were treated with these drugs. The regulation of actin dynamics involves various kinases including Rho–associated kinases ROCKs, and Src family kinases. The ROCK inhibitor Y27632 induced the formation of actin needles running perpendicular to the plasma membrane of A431 cells and increased EGFP-R8 internalisation. By contrast, Src inhibitor PP2 had little effect on both the actin cytoskeleton and EGFP-R8 uptake but completely abrogated the effects of Cyt D on cellular uptake. This demonstrates for the first time that pretreatment of actin with one inhibitor can negate the endocytic effects of another actin inhibitor working on a different target. Overall this study highlights the importance of analysing actin in detail to identify how CPPs and possibly other drug delivery vectors and formulations interact with cells to gain entry. Under defined experimental conditions R8 can modify the actin cytoskeleton and requires a functional or dysfunctional actin network to allow for maximal cellular entry.

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Zhu, Peili. « Anti-hepatocellular carcinoma mode and mechanism of action of antrodia camphorata mycelia ». HKBU Institutional Repository, 2019. https://repository.hkbu.edu.hk/etd_oa/605.

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Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is a common cause of cancer-related death worldwide. Signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in the pathogenesis of HCC. Inhibition of STAT3 signaling has been proposed as a promising strategy for treating HCC. Due to the limitations of conventional therapeutics, increasing attention has been paid to complementary and alternative medicines (CAM) including traditional Chinese medicine (TCM) for the management of HCC. Antrodia camphorata (AC), a medicinal mushroom, is historically used for treating HCC. Pharmacological data showed that extracts and constituents of AC are able to inhibit STAT3 activation. Natural AC is scarce, cultured AC mycelia are becoming alternatives. AC mycelia have been demonstrated to possess anti-HCC properties. We hypothesize that inhibition of the STAT3 signaling pathway contributes to the anti-HCC mechanisms of AC mycelia. To test our hypothesis, we evaluated the safety and investigated the anti-HCC effects of the ethyl acetate fraction of an ethanolic extract of AC mycelia (EEAC); and we further explored the involvement of STAT3 signaling in EEAC's anti-HCC effects. Acute and repeated dose 28-day oral toxicity studies showed that EEAC had no toxicity in rats. The maximum tolerable dose for acute oral toxicity and the no-observed-adverse effects level for repeated dose 28-day oral toxicity of EEAC were higher than 5,000 mg/kg body weight and 1,000 mg/kg body weight, respectively, in rats. In cultured cells, EEAC is less toxic in normal liver-derived cells than in HCC cells. In HepG2 and SMMC-7721 cells, EEAC reduced viability, induced apoptosis, and retarded migration and invasion. In SMMC-7721 cell-bearing mice, EEAC significantly suppressed tumor growth. EEAC inhibited cell proliferation, induced apoptosis and suppressed angiogenesis in tumors. Mechanistic studies showed that EEAC downregulated protein levels of phosphorylated and total STAT3 and JAK2 (an upstream kinase of STAT3) in HCC cells and tumors. In cultured HCC cells, EEAC lowered the protein level of nuclear STAT3, decreased the transcriptional activity of STAT3, and downregulated protein levels of STAT3 targeted molecules. Over-activation of STAT3 in HCC cells diminished the cytotoxic effects of EEAC. STAT3 can be activated by receptor tyrosine kinases (RTKs). Phospho-RTK array assays showed that EEAC significantly inhibited the tyrosine phosphorylation of platelet-derived growth factor receptor-beta (PDGFR-β) in HepG2 cells. EEAC dose-dependently lowered mRNA levels of PDGF BB (a ligand of PDGFR-β) and protein levels of p-PDGFR-β and PDGFR-β in HCC cells. Activating PDGFR-β enhanced STAT3 activation, and inhibiting PDGFR-β blocked STAT3 activation in HCC cells. EEAC reversed PDGF BB induced STAT3 activation in HCC cells. Our data indicate that EEAC exerts anti-HCC effects, and inhibition of PDGFR-β/STAT3 signaling is, at least in part, responsible for these effects. In summary, we have demonstrated that EEAC exerts anti-HCC effects without significant toxicity in vitro and in vivo. We have also demonstrated that inhibition of PDGFR-β/STAT3 signaling contributes to the anti-HCC mechanisms of EEAC. Our findings provide a pharmacological basis for the development of EEAC as a modern anti-HCC agent and for the traditional use of AC in treating HCC. In addition, our data suggest that the PDGFR-β/STAT3 pathway plays a pathogenic role and presents a novel therapeutic target in HCC.

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Mac, Gabhann Liam. « Improving nurse patient therapeutic interactions in acute inpatient psychiatric care through participatory action research ». Thesis, Swansea University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517752.

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35

Smith, Jennifer Ann. « An explorative study of child and youth care workers experiences of "lifespace therapeutic care" ». Thesis, University of the Western Cape, 2004. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=init_4931_1178701317.

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The goal of this research was to explore and describe child and youth care workers lived experiences of life space therapeutic care in a residential setting. Life space refers to the daily living environment, context and situation of children.

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36

Cheung, Chun, et 張俊. « Mechanism of action of Xinmailong, a proprietary Chinese medicine for the treatment of chronic heart failure ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208582.

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Chronic heart failure is one of the commonest fatal diseases in the world. Much work has been done to reveal its complicated pathogenesis and develop effective therapy. Xinmailong (XML), a compound extracted from Periplaneta americana, has been launched on the market in Mainland China as a proprietary medication for treating patients with chronic heart failure. Although it is highly effective, its mechanism of action is still not completely understood. In this study, the results of calcium (〖Ca〗^(2+)) imaging demonstrated that XML increased electrical impulse-induced intracellular calcium ([〖Ca〗^(2+)]i), in H9c2 cells, an rat embryonic cardiomyocytes cell line. This effect was dependent on extracellular 〖Ca〗^(2+) but not the 〖Ca〗^(2+) store from sarcoplasmic reticulum because XML had no effect on thapsigargin -induced 〖Ca〗^(2+) release. The effect of XML was inhibited by ML218-HCl but not nimodipine, indicating that XML interacted with T-type 〖Ca〗^(2+) channels but not L-type 〖Ca〗^(2+) channels. Unlike KB-R7943, which is a sodium calcium exchanger inhibitor, XML did not affect [〖Ca〗^(2+)]i in the absence of electric stimulation, implying that XML did not work on sodium calcium exchanger. Ouabain, a sodium-potassium ATPase inhibitor, increased the electrical impulse-induced [〖Ca〗^(2+)]i and the effect of ouabain and XML were not additive, suggesting that the site of action of ouabain and XML was overlapped. Biochemical assay on phosphate concentration showed that XML was able to inhibit the activity of sodium-potassium ATPase. Our study also demonstrated that XML reduced the production of reactive oxygen species in H9c2 cells. Western blotting showed that such antioxidant properties mechanism might involve the increased expressions of antioxidant enzymes including superoxide dismutase 1, superoxide dismutase 2 and heme oxygenase 1. In conclusion, our study has provided evidence that XML increases [〖Ca〗^(2+)]i level by activating T-type 〖Ca〗^(2+) channels and inhibiting sodium-potassium ATPase. The antioxidant effect of XML may also contribute to the cardioprotective effect of XML but further investigation is required.
published_or_final_version
Pharmacology and Pharmacy
Master
Master of Philosophy

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37

Tian, Songhai, et 田松海. « Proteomic and pharmacological analyses of the mechanism of actions of anticancer gold(I) complexes ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206471.

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Gold complexes have a long history of being used as therapeutic agents, especially in applications against immune diseases such as rheumatoid arthritis. In 1979, an oral gold(I) drug – auranofin (AuRF, brand name as Ridaura®) – was demonstrated to exhibit anticancer properties. Since then, a considerable number of gold(I) complexes have been reported to show remarkable anticancer activities, but the understanding of their mechanism of actions is limited. In the present study, AuRF and several other anticancer gold(I)-phosphine complexes including AuPEt ([Au(triethylphosphine)Cl]) were demonstrated to induce autophagy – a cellular catabolic process of macromolecules and organelles through lysosomal degradation. The induced autophagy involved the accumulation of autophagosomes, which was mediated by the enhancement of autophagy initiation rather than by the blockage of autophagosomes maturation. Moreover, the AuRF and AuPEt induced autophagy was demonstrated to have a pro-survival effect for the cancer cells. To better explore the mechanism of actions of AuRF and other anticancer gold(I) complexes, a subcellular fractionation-based proteomic approach has been developed and optimized. This approach combined the use of subcellular fractionation, protein extraction, HPLC-LTQ-Orbitrap mass spectrometry, and bottom-up protein identification and quantification. By using this approach, the proteome coverage was increased, the complexities of the sub-proteomes were reduced, and the low-abundant organelle proteins were enriched. The nuclear sub-proteomes of AuRF-treated or AuPEt-treated cells were analyzed to identify the significantly regulated transcription regulators and the signaling pathways involved. The analysis delineates the possible AuRF-activated anticancer pathways involving up-regulation of the tumor suppressor cyclin-dependent kinase inhibitor 2A (〖p14〗^ARF), inhibition of the E2F transcription activity, blocking of the translocation of E3 ubiquitin-protein ligase (MDM2) from nucleus to cytoplasm and induction of the tumor suppressor p53. Furthermore, the KeyNode-based pathway analysis was applied to analyze the whole proteomes obtained from merging the sub-proteomes. Alongside the p53 pathway and E2F network, the regulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR, the rate-limiting enzyme of cholesterol biosynthesis) is one of the most up-regulated pathways of AuRF treatment. AuRF also showed significant inhibition to HMGCR activity in vitro with an IC50 value at the micromolar level. The effects of AuRF and AuPEt on the high mobility group box-1 protein (HMGB1), which exhibits distinct functions dependent on its cellular locations, were investigated. Treatment of cells with AuRF or AuPEt resulted in down-regulation of nuclear HMGB1, which is associated with p53-dependent cytotoxicities. The cytoplasmic HMGB1, which can induce autophagy, was found to be up-regulated. The levels of secreted HMGB1, which exhibits pro-inflammatory properties, were reduced, possibly contributing to anti-rheumatoid arthritis actions of AuRF. Collectively, the pharmacological and proteomic analyses in this research of AuRF and other anticancer gold(I) complexes supplement the current knowledge of their mechanism of actions.
published_or_final_version
Chemistry
Doctoral
Doctor of Philosophy

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Butler, Elmien. « Poetic and therapeutic encounters with adolescents ». Pretoria : [s.n.], 2005. http://upetd.up.ac.za/thesis/available/etd-08212007-123522.

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Finch, Krystal. « Adolescent Engagement in Home-Based Treatment : An Action Research Study ». ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/5859.

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Adolescent engagement in home-based treatment is a challenge within the social work field. Studies have suggested that the foundation of clinical practice relies on the clinician's ability to understand the process of engaging adolescents in treatment, which may also include a period of adaptability, relatability, and connectedness within the treatment setting. The purpose of this study is to explore the clinical practice approaches, roles, and experiences utilized in home-based treatment to adolescents residing in a large city in northeastern United States. This study was grounded in the ecological systems theory which provides social workers with an opportunity to assess the relationships between an individuals behaviors and the environment. A qualitative research design was used in this study. Social work clinicians participated in focus groups to address the clinical roles, characteristics, and skills essential for reducing barriers related to adolescent engagement in home-based treatment and explore the clinical practice approaches and knowledge base related to adolescent engagement in home-based treatment, including the areas of competence, respect, empathy, and passion. Data were analyzed using audiotapes of the focus groups, the transcription process, coding, and a reliability check. Findings from this study suggest that effective social work practice techniques depend upon the clinician's ability to engage the adolescent throughout the entire treatment process. The outcomes for this action research study included both challenging and rewarding opportunities for clinicians to increase understanding of characteristics, skills, values, and experiences in providing home-based treatment to adolescents of a large city in the northeastern United States.

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Kojo, Kwofie Samuel. « Development of a Hepatitis C Virus knowledgebase with computational prediction of functional hypothesis of therapeutic relevance ». Thesis, University of the Western Cape, 2011. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_1790_1363781942.

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To ameliorate Hepatitis C Virus (HCV) therapeutic and diagnostic challenges requires robust intervention strategies, including approaches that leverage the plethora of rich data published in biomedical literature to gain greater understanding of HCV pathobiological mechanisms. The multitudes of metadata originating from HCV clinical trials as well as low and high-throughput experiments embedded in text corpora can be mined as data sources for the implementation of HCV-specific resources. HCV-customized resources may support the generation of worthy and testable hypothesis and reveal potential research clues to augment the pursuit of efficient diagnostic biomarkers and therapeutic targets. This research thesis report the development of two freely available HCV-specific web-based resources: (i) Dragon Exploratory System on Hepatitis C Virus (DESHCV) accessible via http://apps.sanbi.ac.za/DESHCV/ or http://cbrc.kaust.edu.sa/deshcv/ and (ii) Hepatitis C Virus Protein Interaction Database (HCVpro) accessible via
http://apps.sanbi.ac.za/hcvpro/ or http://cbrc.kaust.edu.sa/hcvpro/. DESHCV is a text mining system implemented using named concept recognition and cooccurrence based
approaches to computationally analyze about 32, 000 HCV related abstracts obtained from PubMed. As part of DESHCV development, the pre-constructed dictionaries of the
Dragon Exploratory System (DES) were enriched with HCV biomedical concepts, including HCV proteins, name variants and symbols to enable HCV knowledge specific
exploration. The DESHCV query inputs consist of user-defined keywords, phrases and concepts. DESHCV is therefore an information extraction tool that enables users to
computationally generate association between concepts and support the prediction of potential hypothesis with diagnostic and therapeutic relevance. Additionally, users can
retrieve a list of abstracts containing tagged concepts that can be used to overcome the herculean task of manual biocuration. DESHCV has been used to simulate previously
reported thalidomide-chronic hepatitis C hypothesis and also to model a potentially novel thalidomide-amantadine hypothesis. HCVpro is a relational knowledgebase dedicated to housing experimentally detected HCV-HCV and HCV-human protein interaction information obtained from other databases and curated from biomedical journal articles.
Additionally, the database contains consolidated biological information consisting of hepatocellular carcinoma (HCC) related genes, comprehensive reviews on HCV biology and drug development, functional genomics and molecular biology data, and cross-referenced links to canonical pathways and other essential biomedical databases. Users can retrieve enriched information including interaction metadata from HCVpro by using protein identifiers, gene chromosomal locations, experiment types used in detecting the interactions, PubMed IDs of journal articles reporting the interactions, annotated protein interaction IDs from external databases, and via &ldquo
string searches&rdquo
. The utility of HCVpro
has been demonstrated by harnessing integrated data to suggest putative baseline clues that seem to support current diagnostic exploratory efforts directed towards vimentin.
Furthermore, eight genes comprising of ACLY, AZGP1, DDX3X, FGG, H19, SIAH1, SERPING1 and THBS1 have been recommended for possible investigation to evaluate their
diagnostic potential. The data archived in HCVpro can be
utilized to support protein-protein interaction network-based candidate HCC gene prioritization for possible validation by experimental biologists.

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Ravenscroft, Gianina. « A therapeutic approach for the skeletal muscle a-actin based congenital myopathies ». University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2009. http://theses.library.uwa.edu.au/adt-WU2010.0049.

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[Truncated abstract] Mutations in the skeletal muscle -actin gene (ACTA1) have been shown to be one cause of a broad group of muscle disorders all termed the congenital myopathies. Over 170 different mutations have now been identified across all 6 coding exons of ACTA1 in patients presenting with muscle weakness and any one or more of the following histopathological features: nemaline rods, intranuclear rods, fibre-type disproportion, excess of thin filaments and central cores. While the identification of the causative gene has been of great comfort for affected patients and their families, with pre-natal genetic testing becoming available, the ultimate aim is to develop a therapy for these disorders. Of the therapies currently being explored for the muscular dystrophies, up-regulation of an alternative gene seemed to be one of the most promising avenues for treatment of the ACTA1 diseases. Up-regulation of utrophin, the foetal homologue of dystrophin, has been shown to be a promising therapy for the treatment of Duchenne muscular dystrophy. The main aim of my research was to determine whether up-regulation of cardiac -actin, the predominant -actin expressed in foetal skeletal muscle and in the adult heart, could be used as a therapy for the ACTA1 diseases. A proof-of-concept experiment was performed whereby skeletal muscle -actin knock-out (KO) mice (all of which die by postnatal day 9) were crossed with transgenic mice over-expressing cardiac -actin (known as Coco mice) in postnatal skeletal muscle. ... While patients that are ACTA1 nulls have been identified in a number of mainly consanguineous populations, the majority of ACTA1 mutations result in dominant disease in which the mutant protein interferes with the function of the wild-type skeletal muscle -actin. Research described in this thesis also focuses on characterizing two transgenic mouse models of dominant ACTA1 disease at the ultra-structural, cellular and functional level; this is the first step towards a proof-of-concept experiment to determine whether cardiac -actin up-regulation can dilute out the pathogenesis of dominant ACTA1 disease. It has long been noted that patients with ACTA1 disease do not have ophthalmoplegia, even in the most-severely affected individuals. Protein analysis performed on extraocular muscle (EOM) biopsies obtained from humans, sheep and pigs showed that the EOMs co-express cardiac and skeletal muscle -actin, with cardiac -actin comprising 70 % of the striated -actin pool. Thus we propose that sparing of the EOMs in ACTA1 disease is at least in part due to cardiac -actin diluting out the pathogenesis associated with expression of the mutant skeletal muscle -actin. This finding provides further support for the hypothesis that dilution of mutant skeletal muscle -actin in dominant ACTA1 disease by up-regulation of cardiac -actin may be a viable therapy for this group of devastating muscle diseases. The research contained herein has advanced the understanding of the pathobiology of skeletal muscle -actin diseases and provides strong evidence in support of cardiac -actin up-regulation as a promising therapy for these diseases.

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LEONARDI, GIUSEPPA. « Acting as therapeutic support in Parkinson's disease. A Field experiment ». Doctoral thesis, Università degli studi di Catania, 2014. http://hdl.handle.net/20.500.11769/490593.

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In passato l’approccio clinico alla malattia di Parkinson si concentrava essenzialmente sulla sintomatologia motoria: l’attuale tendenza invece sottolinea l’importanza dei sintomi non motori e pertanto si orienta verso un tipo di assistenza più complessa, tesa a potenziare le capacità residue di ogni paziente ed a riabilitare, per quanto possibile, le attività della vita quotidiana compromesse .In tale ottica si va diffondendo l’uso di pratiche artistiche che sembrerebbero influenzare positivamente la sfera emotiva e relazionale dei pazienti, nonché la qualità di vita degli stessi e dei loro familiari. Un gruppo di pazienti affetti da una forma moderata di Parkinson idiopatico, in trattamento stabile con L-dopa e L-dopa agonisti, hanno partecipato, unitamente ad alcuni familiari, ad un laboratorio teatrale, con frequenza settimanale, durato otto mesi e conclusosi con uno spettacolo aperto al pubblico. I pazienti sono stati valutati prima delle attività laboratoriali ed al termine delle stesse usando 8 Scale di Valutazione (H&Y,UPDRS,PDQ8,PDSS,NMSS,FES,GFQ,MMSE), indicative dello stato di progressione della malattia; i risultati delle Scale sono stati confrontati per verificare se la pratica di laboratorio teatrale avesse inciso o meno sulle stesse ed in quale misura. L’analisi dei risultati ha evidenziato modesti miglioramenti nei parametri strettamente motori mentre parametri quali la Memoria, la Capacità di attenzione e di Concentrazione, la Qualità del sonno ma soprattutto gli aspetti relazionali hanno risentito in maniera statisticamente significativa delle attività svolte. Tali dati permettono di affermare che la qualità di vita (QoL) dei pazienti è chiaramente migliorata grazie alla pratica teatrale.
In the past, the clinical approach to Parkinson s disease focussed primarily on motor symptoms, whereas the current trend emphasises the importance of non-motor symptoms, thus moving towards a more complex type of assistance aimed at enhancing each patient s residual ability and, as far as possible, at rehabilitating their impaired daily activities. So, there is a growing amount of artistic activities that appear to positively influence the patients emotional and relational sphere as well as their and their family s quality of life (QoL). Over a period of 8 months, a group of patients with a moderate form of idiopathic Parkinson s disease, on stable L-dopa and L-dopa antagonists, together with a few family members, took part in a weekly theatre workshop culminating in a show given to the public. The patients were evaluated both before and at the end of the eight-month workshop using eight Assessment Scales indicating the state of progression of the disease (H&Y, UPDRS, PDQ8, PDSS, NMSS, FES, GFQ and MMSE). The results of these assessments were then compared to verify if the theatre workshop had had any influence and if so to what extent. The result analysis showed that modest improvements were associated with movement parameters, while parameters regarding memory, attention and concentration, quality of sleep and especially relational aspects were affected in a statistically significant manner, allowing us to say that the patients quality of life (QoL) clearly improved thanks to acting.

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Leonardi, Giuseppa MAria Grazia. « Acting as therapeutic support in Parkinson's disease. A Field experiment ». Doctoral thesis, Università di Catania, 2014. http://hdl.handle.net/10761/1503.

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In the past, the clinical approach to Parkinson s disease focussed primarily on motor symptoms, whereas the current trend emphasises the importance of non-motor symptoms, thus moving towards a more complex type of assistance aimed at enhancing each patient s residual ability and, as far as possible, at rehabilitating their impaired daily activities. So, there is a growing amount of artistic activities that appear to positively influence the patients emotional and relational sphere as well as their and their family s quality of life (QoL). Over a period of 8 months, a group of patients with a moderate form of idiopathic Parkinson s disease, on stable L-dopa and L-dopa antagonists, together with a few family members, took part in a weekly theatre workshop culminating in a show given to the public. The patients were evaluated both before and at the end of the eight-month workshop using eight Assessment Scales indicating the state of progression of the disease (H&Y, UPDRS, PDQ8, PDSS, NMSS, FES, GFQ and MMSE). The results of these assessments were then compared to verify if the theatre workshop had had any influence and if so to what extent. The result analysis showed that modest improvements were associated with movement parameters, while parameters regarding memory, attention and concentration, quality of sleep and especially relational aspects were affected in a statistically significant manner, allowing us to say that the patients quality of life (QoL) clearly improved thanks to acting.

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44

Alrumaih, Ali Mohammed S. « Early environments and neurobehavioural programming : therapeutic actions of antidepressants : neurobehavioural programming during development ». Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/6317.

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Following decades of research on stress and its impact on behaviour, it is now widely accepted that selective psycho-pathologies, in particular clinical depression are more prevalent in humans with prior history of life-stress events. Interest in stress has led to questions about how it might affect the physiology and behaviour of animals exposed indirectly during gestational development. Not unexpectedly gestational stress has been shown to affect the offspring in several ways: endocrine responses to stress are elevated, fear, arousal and affective disturbances are all subject to vary if the pregnant animal is subjected to periods of aversive stimulation. Beginning in 1997, Michael Meaney of McGill University produced a series of publications suggesting that peri-natal events influence offspring and infant development, not via physical discomfort or physiological disturbance, but does so through modifications of maternal behaviour. Highly nurturant mothers (those who engage in active arched-back nursing (ABN), and spend more time licking and grooming (L/G) their pups), programme their offspring with improved cognitive abilities, decreased anxiety and fear, and reduced HPA axis hormone secretion. Low-nurturant mothers, who engage in less ABN and less L/G, tend to programme the opposite responses in their offspring. Our initial foray into this field was to investigate if gestational stress might also produce responses in the offspring via changes in maternal behaviour, and indeed ABN and L/G were reduced in dams which were subjected to gestational stress. We queried why stressed Dams would be less maternal towards their infants, and tested gestationally-stressed Dams in the Porsolt test for depressive-like behaviour. Our results suggested that these stressed Dams were actually depressed and this resulted in less maternal behaviour. Human mothers with depression are also less maternal and have been shown to divest themselves of infant care much like our prenatally-stressed Dams. On this basis we have proposed that gestational stress induced decrements in maternal behaviour represent a novel rat model for postnatal depression with face and construct validities. In the present work we have attempted to replicate the findings of Smythe's group (Smith et al., 2004), and have investigated the potential for antidepressants to alter the influence of gestational stress on maternal behaviours and depressive-like response, and whether or not the offspring are modified by maternal treatment with ant-depressants. Approximately 140 time-mated, lister hooded rats were generated in house, and subjected to gestational stress on days 10-20 (1hr restraint/day) or remained undisturbed in their home cages. Following birth, cohorts of control and stressed Dams were administered vehicle or an antidepressant (imipramine 15mg/kg; or sertraline 10mg/kg) once daily until postnatal day 10. We assessed maternal Porsolt activity, nurturance (ABN, L/G, nest building) and anxiety-like behaviour in the elevated plus maze (EPM). Representative offspring of each Dam's treatment conditions were maintained post weaning and assessed in the Porsolt and EPM to determine if any changes in maternal behaviour elicited by the antidepressants altered their behavioural programming. Our findings confirm that Dams show depressive-like symptoms following gestational stress, and that administration of antidepressants to the Dams reduces depressive-like behaviour and increased maternal care. We propose that rat gestational stress is a putative model for human postnatal depression. Prenatal stress effects on maternal behaviour in the rat Dam represent a novel, and innovative model for human postnatal depression.

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45

Alrumaih, Ali M. S. « Early environments and neurobehavioural programming : Therapeutic actions of antidepressants. Neurobehavioural programming during development ». Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/6317.

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Following decades of research on stress and its impact on behaviour, it is now widely accepted that selective psycho-pathologies, in particular clinical depression are more prevalent in humans with prior history of life-stress events. Interest in stress has led to questions about how it might affect the physiology and behaviour of animals exposed indirectly during gestational development. Not unexpectedly gestational stress has been shown to affect the offspring in several ways: endocrine responses to stress are elevated, fear, arousal and affective disturbances are all subject to vary if the pregnant animal is subjected to periods of aversive stimulation. Beginning in 1997, Michael Meaney of McGill University produced a series of publications suggesting that peri-natal events influence offspring and infant development, not via physical discomfort or physiological disturbance, but does so through modifications of maternal behaviour. Highly nurturant mothers (those who engage in active arched-back nursing (ABN), and spend more time licking and grooming (L/G) their pups), programme their offspring with improved cognitive abilities, decreased anxiety and fear, and reduced HPA axis hormone secretion. Low-nurturant mothers, who engage in less ABN and less L/G, tend to programme the opposite responses in their offspring. Our initial foray into this field was to investigate if gestational stress might also produce responses in the offspring via changes in maternal behaviour, and indeed ABN and L/G were reduced in dams which were subjected to gestational stress. We queried why stressed Dams would be less maternal towards their infants, and tested gestationally-stressed Dams in the Porsolt test for depressive-like behaviour. Our results suggested that these stressed Dams were actually depressed and this resulted in less maternal behaviour. Human mothers with depression are also less maternal and have been shown to divest themselves of infant care much like our prenatally-stressed Dams. On this basis we have proposed that gestational stress induced decrements in maternal behaviour represent a novel rat model for postnatal depression with face and construct validities. In the present work we have attempted to replicate the findings of Smythe¿s group (Smith et al., 2004), and have investigated the potential for antidepressants to alter the influence of gestational stress on maternal behaviours and depressive-like response, and whether or not the offspring¿ are modified by maternal treatment with ant-depressants. Approximately 140 time-mated, lister hooded rats were generated in house, and subjected to gestational stress on days 10-20 (1hr restraint/day) or remained undisturbed in their home cages. Following birth, cohorts of control and stressed Dams were administered vehicle or an antidepressant (imipramine 15mg/kg; or sertraline 10mg/kg) once daily until postnatal day 10. We assessed maternal Porsolt activity, nurturance (ABN, L/G, nest building) and anxiety-like behaviour in the elevated plus maze (EPM). Representative offspring of each Dam¿s treatment conditions were maintained post weaning and assessed in the Porsolt and EPM to determine if any changes in maternal behaviour elicited by the antidepressants altered their behavioural programming. Our findings confirm that Dams show depressive-like symptoms following gestational stress, and that administration of antidepressants to the Dams reduces depressive-like behaviour and increased maternal care. We propose that rat gestational stress is a putative model for human postnatal depression. Prenatal stress effects on maternal behaviour in the rat Dam represent a novel, and innovative model for human postnatal depression.
Ministry of Defence, Prince Sultan Military College of Health Sciences and the Saudi Culture Bureau

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Miller, Mark Russell. « The mechanism of action and therapeutic potential of S-nitrosothiols as novel nitric oxide donor drugs ». Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/24981.

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Recently, two novel S-nitrosothiols, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6,tetra-O-acetyl-β-D-glucopyranose (RIG200) and S-nitroso-N-valerylpenicillamine (SNVP), have been described to have selectivity for endothelium-denuded blood vessels. Therefore, they are particularly appealing in the treatment of conditions where the vascular endothelium is damaged. This thesis describes experiments which further elucidate the mechanism of action and therapeutic of these novel S-nitrosothiols, by comparison to conventional NO donors. The key findings were that S-nitrosothiol-mediated vasodilator activity is a complex process that is dependent on intracellular antioxidant molecules, particularly glutathione. The site of NO release influenced both its susceptibility to inactivation by reactive oxygen species and the extent of sGC involvement. Evidence is also presented to show that the novel S-nitrosothiols do no induce self-tolerance with prolonged administration and remain fully active in nitrate-tolerant vessels. Experiments then focused on the sustained actions of lipophilic S-nitrosothiols in models of endothelial damage. Firstly, GlycoSNAP, an analogue of RIG200 with poor lipophilicity, failed to produce a sustained vasodilatation in endothelium-denuded rat femoral arteries. This result lends weight to the hypothesis that lipophilic S-nitrosothiols exert a sustained vasodilatation in arteries with damaged endothelium through retention in lipid-rich sub-endothelial layers. In the model of balloon angioplasty, the conventional NO donor, glyceryl trinitrate, had no significant effect on platelet adhesion to damaged carotid arteries and also caused a substantial and potentially undesirable fall in blood pressure. In contrast, SNVP caused a >60% reduction in platelet adhesion at a concentration that had minimal effects on blood pressure. The results suggest that these novel compounds may have applications in the treatment of a range of cardiovascular conditions, including atherosclerosis, thrombosis and the prevention of restenosis following bypass grafting and stenting.

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Gasper, Régis. « Infrared spectroscopy as a new tool for the screening of antitumoral agents inducing original therapeutic action ». Doctoral thesis, Universite Libre de Bruxelles, 2010. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210034.

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Actuellement le criblage en vue de la recherche de nouveaux agents antitumoraux se base principalement sur la qualité cytotoxique d’une molécule. Le principal défaut de cette approche est qu’aucune sélection n’est faite sur le mode d’action du médicament. L’objectif de ce travail est la mise au point d’une méthode permettant un classement rapide et objectif du mode d’action de molécules à visée thérapeutique par spectroscopie infrarouge.

La spectroscopie infrarouge est une technique d’absorption de la lumière fournit la signature chimique d’un échantillon. L’excellente qualité du signal rend possible son utilisation comme outil discriminant. En outre, cette technique d’analyse se démarque des autres par son caractère non destructif et la rapidité d’acquisition des données. Elle se révèlerait donc une méthode de choix pour effectuer du criblage de molécules en vue de la recherche de nouveaux agents thérapeutiques.

Dans un premier temps nous avons voulu évaluer la possibilité d’utiliser la spectroscopie infrarouge pour isoler la signature spectrale du mode d’action induit par des concentrations sub-létales de ouabaïne, un composé de la famille des cardénolides, sur une lignée tumorale de prostate. Nous avons montré que cette signature évolue au cours du temps et peut-être corrélée aux données biologiques décrites dans la littérature. Nous avons également mis en évidence pour la première fois une modification de la composition lipidique de la cellule. Cette altération a été caractérisée au cours du temps par spectrométrie de masse.

Nous avons ensuite voulu définir les limites de la méthode. La littérature souligne la diversité des modes d’action que peut induire un agent thérapeutique selon sa concentration. Nous avons montré que cette diversité se reflète sur le spectre infrarouge de cellules tumorales traitées à la ouabaïne en distinguant au moins deux modes d’action distincts, dépendant de la concentration en ouabaïne. Par ailleurs, nous avons montré que la confluence pouvait modifier significativement le spectre infrarouge d’une cellule. Neanmoins cette signature est unique et orthogonale à celle induite par la ouabaïne.

Finalement, nous avons évalué le potentiel de la spectroscopie infrarouge à distinguer des modes d’action induits par des molécules à la structure chimique proche. Nous avons montré qu’il était possible de caractériser spécifiquement chacun des modes d’action. D’autre part nous avons mis en évidence que les modes d’action de molécules issues d’une même classe d’agent thérapeutique conduisaient à des signatures spectrales similaires. Cette partie du travail souligne la possibilité d’utilisation de la spectroscopie infrarouge pour un classement objectif, uniquement basé sur leur mode d’action d’agents thérapeutiques potentiels.

Doctorat en Sciences agronomiques et ingénierie biologique
info:eu-repo/semantics/nonPublished

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Seed, Alison. « Characterisation of the pharmacological actions in humans of multiple vasoactive enzyme inhibitors with therapeutic potential in heart failure ». Thesis, Connect to e-thesis, 2007. http://theses.gla.ac.uk/119/.

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Thesis (M.D.) - University of Glasgow, 2007.
M.D. thesis submitted to the Faculty of Medicine, Dept. of Medicine and Therapeutics, University of Glasgow, 2007. Includes bibliographical references. Print version also available.

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Muwanga, Catherine. « An assessment of Hypoxis hemerocallidea extracts, and actives as natural antibiotic, and immune modulation phytotherapies ». Thesis, University of the Western Cape, 2006. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_3303_1184589097.

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In South Africa, the crude aqueous extract from Hypoxis hemerocallidea is used by AIDS patients to treat opportunistic infections, such as tuberculosis. The rapid emergence of multidrug-resistant tuberculosis, and extreme drug resistant tuberculosis, in recent years, is a major threat to human health. The treatment of TB, nosocomial bacterial infections, and fungal infections is now a clinical challenge, especially in the immuno-compromised individual. There is a dire need for novel antibiotic alternatives with phytotherapies and plant-derived compounds as potentially promising alternatives. The main objective of this study was to investigate the antimycobacterial activity of Hypoxis hemerocallidea, a South African medicinal plant, using Mycobacterium smegmatis.

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Brundula, Sodja Veronika. « Inhibiting T cell migration as a therapeutic strategy for Multiple Sclerosis, minocycline and its mechanisms of action ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0019/MQ55198.pdf.

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