Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Proefschrift Maastricht. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Maastricht. / Met lit. opg. - Met een samenvatting in het Nederlands.

Existing pharmacokinetic monitoring tools for cyclosporine fail to correlate with clinical response. In dogs, pharmacodynamic monitoring of nuclear factor of activated T cell (NFAT) regulated cytokines is thought to provide a better overall evaluation of the immune response to cyclosporine than blood levels; however, such monitoring tools are not available in cats. In this study, we designed and optimized a protocol for maximal T lymphocyte stimulation in cats. This is the first step in the development of a pharmacodynamic monitoring tool for cyclosporine in cats based on expression of NFAT-regulated cytokines. We also confirmed that cyclosporine has anti-lymphocytic properties in cats, and we were the first to document induction of apoptosis by cyclosporine in cats. Differences in individual patient response to cyclosporine may be influenced by apoptotic response of lymphocytes to cyclosporine. Additional studies are required to optimize and validate polymerase chain reaction monitoring of NFAT-regulated cytokines for cyclosporine-mediated immunosuppression.

Thesis (M.Sc.)--Memorial University of Newfoundland, School of Pharmacy, 1997. / Typescript. Bibliography: leaves 116-141.

Cyclosporin A (CsA) was incubated at concentrations of 5.0 x 10⁻⁶ M for 72 hours, and at concentrations of 1.0 and 0.5 x 10⁻⁶ M for 30 days with kangaroo rat proximal tubular epithelial cells (PtK₂) in order to evaluate its effects on the cytoskeleton. Alterations in the cytoskeleton were assessed by indirect immunofluorescence of viable cells, and by two dimensional electrophoresis of a high salt extract from the cells. There is a selective alteration of the cytokeratin intermediate filament organization in both the short term (5 x 10⁻⁶ M, 72 hr) and long term (1 and 0.5 x 10⁻⁶ M, 30 days) exposures. There are either peri-nuclear rings formed or the formation of a single aggregate clump of the cytokeratins within the cytoplasm. Other components of the cytoskeleton, the microtubules and the microfilaments remain unaffected at both short term and long term exposures. Along with this cytokeratin alteration in CsA exposed cells is the decrease or elimination of an acidic triplet of cytokeratin protein monomers, human equivalent K15 (50 kd), K16 (48 kd), K17 (46 kd). This may be related to CsA-associated nephrotoxicity.

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Immune-mediated hemolytic anemia (IMHA) is one of the most common causes of anemia in dogs. Despite aggressive therapy, there is a 50% mortality rate in IMHA patients, and the most common cause of death is thromboembolic disease, particularly pulmonary thromboembolism. With the high thromboembolism rate in dogs with IMHA, anti-platelet therapy with aspirin can be a life-saving preventative therapy. Along with anti-platelet therapy, immunosuppressive therapy is needed to decrease erythrocyte destruction. Cyclosporine has become a popular medication for immunosuppression in IMHA patients. Unfortunately, recent human reports have suggested that cyclosporine could activate platelets and contribute to a hypercoagulable state. With the goal of improving therapy, these studies investigated the role aspirin plays in inhibiting platelet function and cyclooxygenase expression, an enzyme that enhances platelet reactivity. The effect of cyclosporine on platelet reactivity and hypercoagulablity was investigated to determine if this medication would create activated platelets and a prothrombotic state.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2004. / Bibliography: leaves 147-168.