The primary aim of this work was to provide an alternative method of synthesis of the non-steroidal anti-inflammatory drug copper indomethacin (Cu-Indo) and to produce alternative forms of the drug to increase its marketability. Dense gases as anti-solvents were used to achieve these aims. The study involved the synthesis, purification, micronisation and co-precipitation of Cu-Indo with polyvinylpyrrolidone (PVP) using dense carbon dioxide as an anti-solvent. Initially the volumetric and solubility behaviours of the solvent???anti-solvent systems were investigated to determine the optimum processing conditions. The solubility of Cu-Indo in an expanded solution was found to be a complex function of the solvent and other solutes. Copper indomethacin was successfully synthesised and purified in a single vessel using dense carbon dioxide as an anti-solvent. Drug yields of 98 % and purities near 100 % were achieved at optimum conditions with the advantages of less residual solvent in the drug, less solvent waste, reduced processing time and increased yields over the conventional synthesis process. Copper indomethacin was produced in a variety of morphologies and particle sizes using dense carbon dioxide as an anti-solvent. An investigation of the effect of process parameters on the particle characteristics showed that solute concentration was the dominant variable. Spherical particles with diameters less than 8 mm were obtained at optimum conditions. The immediate benefit of micronising Cu-Indo was demonstrated with an eight fold increase in dissolution rate when compared to the conventionally produced drug. Polyvinylpyrrolidone was successfully co-precipitated with Cu-Indo using dense carbon dioxide as an anti-solvent. The PVP???Cu-Indo co-precipitates were found to increase the solubility of the drug in ethanol with a 36 fold solubility enhancement at optimum conditions. The use of dense carbon dioxide as anti-solvent in this work demonstrates the potential of the GAS and ASES processes in the pharmaceutical industry. Copper indomethacin was synthesised, purified and micronised in a single vessel at a substantial saving in terms of time and solvent usage. The micronisation of Cu-Indo and the formation of the PVP???Cu-Indo co-precipitate provided alternative forms of the drug substantially increasing its marketability.

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 60-65).

Thesis (Ph.D.)--York University, 2004. Graduate Programme in Psychology. / Typescript. Includes bibliographical references (leaves 121-136). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://wwwlib.umi.com/cr/yorku/fullcit?pNQ99154

Ovarian cancers often develop resistance mechanisms against the standard platinum and taxane chemotherapy, which indicates the need for novel therapeutics to improve patient outcome. In vitro assays were performed to assess the effects and mechanism of action of a novel peptide, GAP-107B8, on ovarian cancer cell viability. Xenograft models were used to determine GAP-107B8’s effects on tumour burden in immune-incompetent mice. GAP-107B8 significantly reduced cell viability in ovarian cancer cell lines, although no synergistic effects with carboplatin were observed. This reduction in cell viability was due in part to apoptosis and may involve mechanisms leading to decreased pAKT, but without any change in pPKC levels. In vivo, GAP-107B8 had no effect on ovarian tumour burden, but significantly reduced ascites volume. The findings suggest that GAP-107B8 can reduce some malignant characteristics of cancer cells in vitro and in vivo and should be evaluated further as a potential therapeutic for ovarian cancer.

This primarily qualitative research study examined the views of first and second year nursing students regarding leisure and its relationship to health. Thirty-two nursing students reflected on their own lived experiences of leisure by completing an on-line survey. Three of the students added depth to the initial survey results by completing the Leisure Attitude Measure (LAM) and participating in a focus group. This study examined how the nursing students understood the concept of leisure and the connection between leisure and health. As well, it explored the implications that this understanding has on Therapeutic Recreation (TR) professionals as they conduct advocacy and education sessions on the field of TR with other members of the interdisciplinary health care team.<p> The students responses were analyzed using an inductive technique with themes emerging from the data. As a group, the students responses touched on many of the components of leisure and connections to health outlined in the literature. However, individual responses were often missing key aspects related to the subjectivity of leisure, the holistic nature of leisure and the potential of leisure and TR in contributing to the treatment of patients. The responses suggest a number of implications for TR professionals as they prepare and deliver educational and advocacy sessions for other staff. From a broader sense, the data raise some areas worth considering in terms of the potential for leisure education within educational and societal contexts.

This primarily qualitative research study examined the views of first and second year nursing students regarding leisure and its relationship to health. Thirty-two nursing students reflected on their own lived experiences of leisure by completing an on-line survey. Three of the students added depth to the initial survey results by completing the Leisure Attitude Measure (LAM) and participating in a focus group. This study examined how the nursing students understood the concept of leisure and the connection between leisure and health. As well, it explored the implications that this understanding has on Therapeutic Recreation (TR) professionals as they conduct advocacy and education sessions on the field of TR with other members of the interdisciplinary health care team.<p> The students responses were analyzed using an inductive technique with themes emerging from the data. As a group, the students responses touched on many of the components of leisure and connections to health outlined in the literature. However, individual responses were often missing key aspects related to the subjectivity of leisure, the holistic nature of leisure and the potential of leisure and TR in contributing to the treatment of patients. The responses suggest a number of implications for TR professionals as they prepare and deliver educational and advocacy sessions for other staff. From a broader sense, the data raise some areas worth considering in terms of the potential for leisure education within educational and societal contexts.

Dissertation (Ph.D.)--University of Toledo, 2009. / Typescript. "Submitted as partial fulfillment of the requirements for the Doctor of Philosophy in Psychology." Bibliography: leaves 95-107.

Dissertation (Ph.D.)--Auburn University,2006. / Abstract. Includes bibliographic references (p.69-83).

Heterologous enzymes have been investigated for a variety of therapeutic applications, including the treatment of a number of cancers that are sensitive to the systemic depletion of specific amino acids. One such example is acute lymphoblastic leukemia (ALL) for which enzyme-mediated L-Asparagine (L-Asn) depletion by the Escherichia coli L-Asparaginase II (EcAII) has been proven critical for treatment. However, the repeated or prolonged therapeutic administration of such enzymes is restricted by their immunogenicity, which frequently results in the generation of anti-enzyme antibodies that may in turn mediate a variety of adverse hypersensitivity reactions and neutralization of the enzymes themselves. Thus, while the therapeutic efficacy of asparaginase is well established, a significant number of patients still develop adverse immune responses to the enzyme. Here, we have developed and explored novel strategies towards engineering an asparaginase with reduced immunogenicity for ALL therapy. First, we identified and investigated human enzymes that putatively shared functional similarity to asparaginase with the long-term aim of engineering such enzymes to acquire biochemical and pharmacological properties requisite for eventual therapeutic application. In one study, we described the bacterial expression and characterization of the human asparaginase-like protein 1 (hASRGL1). We presented evidence that hASRGL1 exhibited an activity profile consistent with enzymes previously designated as [Beta]-aspartyl peptidases, which had only been previously identified in plants and bacteria. Similar to non-mammalian [Beta]-aspartyl peptidases, hASRGL1 was revealed to be an N-terminal nucleophile (Ntn) hydrolase whereby Thr168 serves as the essential Ntn for both intramolecular processing and catalysis. In a second study, we described the optimized bacterial expression and biochemical characterization of the human N-terminal asparagine amidohydrolase 1 (hNTAN1). We demonstrated that hNTAN1 catalysis is dependent upon direct involvement of a thiol group, and subsequently identified Cys75 as an essential residue that may act as the catalytic nucleophile. Further, we presented the first description of hNTAN1 kinetics, secondary structure composition, and thermal stability. Second, we devised and validated a novel therapeutic deimmunization approach by combinatorial T-cell epitope removal using neutral drift. We showed that combinatorial saturation mutagenesis coupled with a robust neutral drift screen enabled the isolation of engineered EcAII variants that contained multiple amino acid substitutions yet exhibited catalytic efficiencies nearly indistinguishable to that of the parent enzyme. Three regions of EcAII were computationally identified as putative T-cell epitopes and then subjected to saturation mutagenesis at 4 positions (per region) believed to be critical for MHC-II binding. The resulting libraries were then sequentially subjected to a neutral drift FACS screen in order to isolate EcAII mutants that retained wild-type function. Pools of neutral drift variants were then computationally evaluated for MHC-II binding and those that displayed scores indicative of compromised binding were purified and biochemically characterized. Finally, T-cell activation assays and antibody titers in HLA-transgenic mice were used to evaluate T-cell epitope removal and immunogenicity, respectively. Ultimately, we revealed that mice immunized with an EcAII neutral variant containing 8 amino acid substitutions -- 3 of which were non-phylogenetically conserved -- within computationally predicted T-cell epitopes, displayed a significant 10-fold reduction in serum anti-EcAII IgG titer relative to mice similarly immunized with the parent enzyme. / text

published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy