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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

Clinical resistance to platinum chemotherapy in ovarian cancer

Newton, C. January 2009 (has links)
Platinum drugs are the most active agents in ovarian cancer. Their cytotoxicty results from DNA crosslinking. High tumour response rates are seen, but 80 % of patients relapse. Major mechanisms of platinum resistance in patients remain to be established. We have studied DNA interstrand crosslinking and its repair in response to ex vivo treatment with cisplatin in forty patients with ovarian cancer using the single cell gel electrophoresis (comet) assay. Tumour cells from resected tumours or tumour and mesothelial cells from ascites were obtained from chemonaive patients and those relapsing after platinum-based therapy. The average percent decrease in tail moment at the peak of crosslinking was 61.1% 9.25 in 34 pre-chemotherapy patient samples following treatment with lOOuM cisplatin. In 14 post-chemotherapy patient samples it was 58.1% 9.94. The average percentage repair at 24 hours was 3.6% 18.89 in pre- chemotherapy patients and 44.6% 43.4 for post-chemotherapy patients (p < 0.001). In 6 paired samples, before and after chemotherapy the average percentage repair at 24 hours was 7.2% 12.64 increasing to 69.5% 23.42 after chemotherapy. Differences in cell cycling, and cell signalling gene expression levels using microarray analysis was found, between pre- and post-chemotherapy patients. Real time PCR was also used to investigate the levels of ERCC1 (excision-related cross complementation group 1) in 3 of these paired patient samples, which was found to be increased by an average of 14.4% +/-0.8% in 3 post-chemotherapy samples. In ten pre-chemotherapy and seven post-chemotherapy patient tumours incubated ex vivo with 50uM melphalan, the percent decrease in tail moment at the peak of crosslinking was 41.4+11.2, and 44.6 7.6, respectively. 24 hours later the percentage repair was 3.1 .25.6 for untreated and 2.8 26.3 for treated tumours. In conclusion, repair of DNA interstrand crosslinks appears to be an important mechanism of clinical platinum resistance in ovarian cancer. Repair of melphalan crosslinks is unaffected.

Peptide rotaxanes as potential prodrugs

Potok, Stephanie January 2004 (has links)
Peptides are potential therapeutic agents involved in a wide range of biological processes. In principle, rotaxanes can be used as novel prodrug delivery systems to overcome the problems of peptide degradation <i>in vivo</i> and their poor membrane transport permeability. The presence of the macrocycle around the peptide thread acts as a protective shield against peptidases and modifies its cell membrane transport characteristics. However, the classical ‘clipping’ method of rotaxane formation is mainly limited to dipeptide sequences since the presence of intramolecular hydrogen bonds in longer threads causes folding of the backbone, preventing good interactions with the precursor to the macrocycle. This thesis focused on the synthesis of short peptide rotaxane building blocks. Their elongation on both sides of the peptide backbone was then applied to the straightforward synthesis of oligopeptide [2] and [3]rotaxanes in very good yields.

The synthesis and study of chemically modified anti-HIV antisense oligonucleotides

Graham, Duncan January 1996 (has links)
It has been reported that the presence of a hydrophobic moiety at the 5-position of 2'-deoxyuridine increases duplex stability when incorporated into an oligonucleotide. A series of 2'-deoxyuridine analogues modified at the 5-position have been synthesised. The stability of a 12mer duplex containing these residues was analysed by ultraviolet melting studies. Of the groups tested 5-propynyl-2'-deoxyuridine imparted greatest stability on the duplex. Thermodynamic parameters show that the reason for increased stability arises from a decrease in enthalpy which is related to the base stacking process. Ultra high field NMR was used to elucidate the 3D structures of a deoxydodecanulceotide containing 5-propynyl-2'-deoxyuridine residues at two different positions. These structures show an increased π-π overlap with the base on the 5'-side of the modified base. This suggests the degree of stabilisation imparted by the propyne moiety may be sequence dependent. Cellular uptake of antisense oligonucleotides is particularly low. In an attempt to improve uptake a cholesterol moiety linked by two different lengths of alkyl spacer was attached to an antisense oligonucleotide. Anti-HIV activity of the cholesteryl conjugated oligonucleotide was improved relative to the unmodified oligonucleotide. Pharmacokinetic properties of the cholesteryl conjugated oligonucleotide was less than that of the unmodified oligonucleotide.

The interactions of antibiotics with eukaryotic ribosomes

Hobden, Adrian N. January 1978 (has links)
Precipitation of peptidyl-tRNA by cetyltrimethylammonium bromide affords an extremely convenient and accurate means of following the reaction of nascent polypeptides with puromycin. Using this assay, I have investigated the modes of action of several antibiotics which inhibit polypeptide chain elongation. The polypeptide, alpha sarcin, has been shown to inhibit the binding of aminoacyl-tRNA to the ribosomal 'A' site as have the antibiotics, chartreusin and emetine. Additionally, it has been confirmed that sparsomycin and trichodermin inhibit the peptidyl transferase whereas cycloheximide probably inhibits translocation. The technique for measuring peptidyl-tRNA concentrations has also been used to detect inhibitors of initiation of protein synthesis. By this and other techniques, homoharringtonine has been shown to inhibit a step in initiation - possibly the same step as that inhibited by the chemically-unrelated antibiotic T-2 toxin. Cell-free extracts of S. cerevisiae and M. verrucaria have been prepared which are very active in poly U-directed protein synthesis. These extracts have been used to study resistance to the 12,13 epoxytrichothecene group of toxins either in a yeast mutant, strain TR1, or in the organism M. verrucaria which produces several 12,13 epoxytrichothecenes. Both strain TR1 and M. verrucaria are resistant to T-2 toxin in vitro because of features of their 60S ribosomal subunits. The effect of the 12,13 epoxytrichothecene, trichodermin, on poly U-directed protein synthesis by yeast cell-free extracts was also investigated. It was found that there were apparently two types of synthesis - one sensitive and one insensitive to trichodermin. The ratio of the two types of synthesis appeared independent of the manner in which the ribosomes were prepared but was influenced by ion concentrations and the mode of preparation of the high-speed supernatant fraction (S100). Both types of poly U-directed protein synthesis involved production of polyphenylalanine rather than peptidy1-polyphenylalanine. Cell-free extracts capable of poly U-directed protein synthesis were also produced from strains of the 12,13 epoxytrichothecene-producing organisms F. poae, F. sporotrichiodes and F. equiseti and the fungi, A. giganteus, which produces alpha sarcin. All the organisms were sensitive to their products in vitro but resistant in vivo.

Studies on the bioavailability of drugs from peroral aqueous suspensions

Barzegar-Jalali, Mohammed January 1979 (has links)
No description available.

Hydrogel-formimg microneedles for therapeutic drug monitoring

Caffarel-Salvador, E. January 2014 (has links)
Therapeutic drug monitoring (TOM) focuses on measurement of drugs with narrow therapeutic windows. Inappropriate concentrations of these drugs can elicit either an absence of therapeutic response or toxic effects. Microneedles (MN) have previously been studied for their ability to painlessly penetrate the stratum corneum, allowing transdermal delivery of various compounds. Interest in MN technology to sample analytes is increasing due to their minimally-invasive characteristics when compared to conventional needles. . . To overcome problems associated with the use of conventional needles, this study aimed to identify the most suitable polymeric MN array design and utilise this, for the first time, as a sampling device capable of imbibing large amounts of fluid for TOM. Hydrogel-forming MN arrays were fabricated from blends of poly(methyl vinyl ether-eo-maleic acid) crosslinked with poly(ethylene glycol) both with and without pore-forming agents. These MN were used in combination with reverse iontophoresis and hygroscopic Iyophilised tablets to further enhance fluid uptake by polymeric matrices. Theophylline, a bronchodilator with a narrow therapeutic window, was chosen as the model drug of the study. A high-performance liquid chromatography (HPLC) method was developed and validated for detection of theophylline. This study proved the capacity of hydrogel-forming MN to take up theophylline, in vitro and in vivo, and release it in water solution for HPLC quantification. Theophylline was successfully detected and quantified from 12 of 24 MN after 1 h insertion in the back of rats dosed with 10 mg theophylline/kg body mass. While this study posed certain challenges, including problems optimising HPLC methodology and difficulties designing a method to extract theophylline in vivo, the potential of MN as a novel in vivo TOM technology with significant clinical potential was proven. Ideally, given the findings of this study, future work will focus on the use of hydrogel-forming MN for TOM in human volunteers.

Bioactive peptides from phyllomedusinae

Xinping, X. January 2014 (has links)
For thousands of years, Nature has' been considered to be essential for human beings for the treatment of their diseases. Amphibians are an important component of the Animal Kingdom and have played a significant role in sourcing many active compounds and some therapeutics. In the course of this research, genomic and proteomic techniques have been used to investigate the bioactive peptides from the skin secretions of four American amphibian species: the Central American red-eyed leaf frog, Agalychnis callidryas~ the South American orange-legged leaf frog, Phyllomedusa hypochondrialis, Rohde's leaf frog, Phyllomedusa rohdei and the Giant Mexican leaf frog Pachymedusa dacnicolor. The synthetic peptides all exhibited significant biological activities. Medusins were a novel family of antimicrobial peptides found in all species investigated and all possessed a broad-spectrum of antibiotic activity. Phylloseptins were found to be active against both planktonic bacteria and those within biofilms. Bradykinin-like peptides (BRPs) exhibited significant and selective activities on a range of mammalian smooth muscle preparations and one was identified as a B2 receptor antagonist using the rat tail artery. These discoveries of novel peptides from amphibian skin secretions have enriched our knowledge of bioactive peptides from this source and may provide the basis for several drug development programmes.

Peptide self-assembly in biomaterial design

Currie, Keith William John January 2014 (has links)
The process of self-assembly of short synthetic peptides into highly complex organised hydrogel structures is currently of interest due to the fact that these can potentially form a commercially viable means of producing novel biomaterials with a diverse range of functions and applications in drug delivery and tissue engineering. This thesis aimed to design a range of bespoke short synthetic peptides and examine the effects of varying the chemistry of the N-terminus on the ability of certain dipeptide sequences to form competent hydrogelators. As the design of competent peptide hydrogelators from first principles remains a challenge in this field, an examination of the effects of N-terminus chemistry was warranted to further understand the role that the N-terminus plays in either aiding or hindering dipeptide self-assembly. Following the successful solid-phase synthesis ofa library of twenty-eight dipeptides, these compounds were tested for their ability to form hydrogels following gelation triggering using solvent based induction using DMSO and via a pH change based induction using G1ucono-delta-lactone (GdL). Eleven successful hydrogelators were identified in the DMSO induction tests and hydro gels formed using this method were assessed for secondary structure, micro-morphology and mechanical properties using FTIR, TEM and rheology respectively. The presence of aryl-oxyethyl carbonyl and ethyl carbonyl linkers in the N-terminus appeared to hinder gelation via DMSO triggering. Twenty successful hydrogelators were identified when GdL was used to cause a pH change induction. The presence of oxyethyllinker groups in the N-terminus also appeared to hinder the gelation of compounds when using pH induction. Following the analysis of the secondary structure and mechanical properties of hydro gels formed using DMSO or pH induction methods, the compounds were then tested for in vitro cytotoxicity towards the human cell lines HeLa and HaCaT. Several novel compounds were identified as candidates for further in vitro and in vivo studies.

Sustained release biodegradable ocular drug delivery systems

McMillan, Hannah Louise January 2015 (has links)
Delivery of drugs to the posterior segment of the eye is notoriously difficult and unfortunately many chronic conditions of the posterior segment often lead to sight-loss if not treated effectively. Current methods of delivery such as topical drops result in poor bioavailability at the back of the eye, while the blood brain retina imposes restrictions on the entry on drugs into the eye delivered by the systemic system. The gold-standard method for delivery of therapeutic concentrations of drugs is intravitreal delivery, which involves an injection into the vitreous cavity. Although this provides therapeutic levels of drugs, numerous injections are required to maintain these concentrations, and the frequency of injection can cause various adverse effects such as retinal detachment, vitreous haemorrhage and endophthalmitis. The present study investigates the potential use of solvent-induced in situ forming implants (ISFI) as a method of delivering drugs in a prolonged manner to the posterior segment of the eye. These systems are composed of a water-insoluble polymer dissolved in an organic solvent. Their low viscosity allows for easy administration through small-bore needles (e.g. 27 gauge) and on contact with an aqueous environment, such as the vitreous humour, phase inversion through solvent exchange takes place resulting in a biodegradable polymeric implant that can release drugs for an extended period. . As another method to improve posterior drug delivery in a minimally-invasive manner, microneedles (MN) were used to inject small amounts of ISFI formulation into sclera. Drug release and permeation stUdies across sclera indicated that the use of MN did indeed improve scleral permeation, with potential to allow posterior drug delivery from an intrascleral depot. From investigations carried out in the present study, ISFI show promise in transforming drug delivery to the eye and therefore possibly preventing the loss of sight in numerous individuals.

Characterisation of aerosols generated by pressurised metered dose inhalers

Harang, Marie January 2013 (has links)
For over half a century, pressurised metered dose inhalers (pMDIs) have been the most sold inhaler devices for the treatment of lung diseases. However, they suffer from significant drug deposition in the mouth and throat, mainly due to the aerosolisation of large and fast-moving droplets. This causes a high occurrence of side effects and is wasteful of drug. They are also affected by a low consistency of dosing and as a result users might not benefit from maximal device efficiencies. The hypothesis of this work was that the performance of pMDIs is dependent on numerous factors which might alter the characteristics of their particles and their deposition location within the respiratory tract. For example, it was thought that the variations in actuation forces of pMDIs and temperatures at which they are used might contribute to their low consistency. A one-dimensional Matlab computational model was developed in order to calculate spray properties at the exit of the device where experimental measurements are difficult to conduct. The model simulated the discharge of pure HFA134a formulations and HFA134a-based suspension formulations containing uticasone propionate, the latter representing a commercially available formulation. The results showed that the actuation force of a 'healthy' adult led to a higher valve opening rate and to the aerosolisation of smaller droplets than the actuation force provided by a 'weak' adult. The model also showed that an increase of temperature led to the aerosolisation of smaller droplets. The model was validated using impaction measurements and laser techniques. The next generation impactor (NGI) experiments revealed the importance of actuation forces on the throat deposition. Automated actuation forces with high valve opening rates led to a lower throat deposition than a manual actuation force with low valve opening rate.

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