Chronic total occlusions are a common problem in patients with coronary artery disease. The primary barrier to successful percutaneous coronary intervention is inability to cross the lesion with a guidewire. We seek to characterize polymer microspheres as a controlled delivery mechanism for collagenase and VEGF, novel intralesional therapies being investigated to alter CTO structural properties. Release profiles for protein-loaded PLGA [poly(lactic-co-glycolic acid)] microspheres showed sustained BSA and VEGF release over eight and 48 hours respectively. Polymer degradation products had no impact on endothelial cell growth and protein bioactivity was maintained post-release. In vivo localization of microsphere-released collagenase was not possible due to low concentrations remaining at the site. Histology confirmed microspheres remained in the collagen-dense, proximal 15 mm of the lesion, likely altering the structural integrity of the plaque.

Chronic total occlusions are a common problem in patients with coronary artery disease. The primary barrier to successful percutaneous coronary intervention is inability to cross the lesion with a guidewire. We seek to characterize polymer microspheres as a controlled delivery mechanism for collagenase and VEGF, novel intralesional therapies being investigated to alter CTO structural properties. Release profiles for protein-loaded PLGA [poly(lactic-co-glycolic acid)] microspheres showed sustained BSA and VEGF release over eight and 48 hours respectively. Polymer degradation products had no impact on endothelial cell growth and protein bioactivity was maintained post-release. In vivo localization of microsphere-released collagenase was not possible due to low concentrations remaining at the site. Histology confirmed microspheres remained in the collagen-dense, proximal 15 mm of the lesion, likely altering the structural integrity of the plaque.

Graduation date: 1993

The purpose of the current study was to develop a manualized treatment for fibromyalgia syndrome (FM) and to examine the efficacy of the treatment in a randomized controlled clinical trial. FM is a chronic musculoskeletal pain disorder characterized by tender points and generalized pain. Depression, chronic fatigue, and sleep disturbance are common. A biopsychosocial model served as a framework for understanding FM by integrating psychological, social, and physical factors. Cognitive-behavioural therapy (CBT), an empirically validated treatment for arthritis, has also been used with FM patients in an attempt to improve pain control, reduce disability, and increase self-efficacy. Overall, the attention/placebo controlled studies employing CBT as a treatment for FM show that it is not superior to a credible attention placebo. The current study attempted to combine the necessary components of CBT with interpersonal therapy to address relational patterns and personality characteristics that can affect ability to cope with chronic pain. One hundred and five women diagnosed with FM by a rheumatologist were randomly assigned to the CBT-interpersonal treatment condition or an attention-control condition. There were 8 treatment groups with a mean of 6-7 participants in each. The treatment consisted of weekly 2-hour sessions over 8 consecutive weeks. Outcome measures included: FM impact, pain, health care utilization, depression, coping, and self-efficacy. An intention-to-treat analysis was conducted. Results showed that the impact of FM symptoms was reduced following treatment compared to the control group and this was statistically and clinically significant, but was not maintained at 3-month follow-up. Significant improvements were also observed in coping strategies, some of which were maintained at follow-up. Importantly, self-efficacy improved significantly following treatment compared to the control group. Self-efficacy beliefs have been related to pain, coping efforts, disability, and psychological functioning. Directions for future research may include a focus on long-term maintenance of treatment gains that may be mediated by improvements in self-efficacy. There is strong evidence that changes in self-efficacy are enduring and affect changes in health behaviours and health status.

An experimental and modeling investigation of nitroxide-mediated radical polymerization (NMRP) of styrene using 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as controller is presented. The objective was to examine the effect of temperature, controller to initiator molar ratio, and initiation mode on conversion, molecular weight and polydispersity development, and also to generate a source of reliable experimental data for parameter estimation and further model validation purposes. Polymerizations with a bimolecular initiator (Benzoyl Peroxide; BPO) were carried out at 120 and 130°C, with TEMPO/BPO molar ratios of 0.9 to 1.5. The effects of temperature and TEMPO/BPO ratio on polydispersity, molecular weight averages and conversion (rate) were studied. Results indicate that increasing temperature increases the rate of polymerization while the decrease in molecular weights is only slight. It was also observed that increasing the ratio of TEMPO/BPO decreased both the rate of polymerization and molecular weights. To investigate the contribution of thermal self-initiation in NMRP of styrene, thermal NMRP of styrene with TEMPO in the absence of initiator was carried out at 120 and 130°C. The results were compared with regular thermal polymerization of styrene and NMRP of styrene in the presence of BPO. It was observed that although the thermal polymerization of styrene can be controlled to some extent in the presence of TEMPO to provide lower polydispersity polystyrene, the polymerization was never as controlled as that obtained by a BPO initiated NMRP. Additional experiments were conducted with a unimolecular initiator and compared to the corresponding bimolecular system with the same level of nitroxide at 120°C, to gain additional insight on the advantages and disadvantages of each system. In addition, the importance of diffusion-controlled (DC) effects on the bimolecular NMRP of styrene was assessed experimentally by creating conditions where DC effects may be present from the outset. The results were corroborated by mathematical modeling and it was concluded that DC-effects are weak in the NMRP of styrene, even in the presence of “worst case scenario” conditions created. Finally, a mathematical (mechanistic) model based on a detailed reaction mechanism for bimolecular NMRP of styrene was presented and the predicted profiles of monomer conversion, molecular weight averages and polydispersity were compared with experimental data. Comparisons suggest that the present understanding of the reaction system is still inconclusive, either because of inaccuracy in values of kinetic rate constants used or because of some possible side reactions taking place in the polymerization system that are not included in the model. This was somewhat surprising, given that papers on controlled radical polymerization, and NMRP in particular, have clearly dominated the scientific polymer literature in the last fifteen years or so.

This thesis presents the results of a study on the kinetics of nitroxide-mediated radical polymerization of styrene with a unimolecular initiator. The primary objective was to obtain a more comprehensive understanding of how a unimolecular-initiating system controls the polymerization process and to clarify the effects of various reaction parameters. Previous work in this field has met with some difficulties in the initiator synthesis, such as low yield and inconsistency of molecular weight. These problems were overcome by adjusting reaction conditions and procedures. Better yields of initiator with consistent molecular weight were produced by the improved methods. Control of polymerization rate and polymer molecular weight in unimolecular nitroxide-mediated radical polymerization was studied by looking at the effects of the three main factors: initiator concentration, temperature, and the initiator molecular weight on polymerization rate, molecular weight and polydispersity. Results indicated that increasing the initiator concentration had no effect on polymerization rate at low conversion, but led to lower polymerization rate at high conversion; higher initiator concentration led to lower molecular weight of the resulting polymer. It was also found that temperature significantly increased the polymerization rate, yet had no effect on number-average molecular weight, Mn, at low conversion, while it caused a plateau at high conversion levels; there was no effect on weight-average molecular weight, Mw, through the whole conversion range. In addition, increasing initiator molecular weight was found to have no effect on either polymerization rate or molecular weight. The experimental molecular weights of the unimolecular system were compared to theoretical molecular weights based on ideal controlled radical polymerization (CRP). The results were found to be close to the theoretical values. This confirmed the advantages of the unimolecular system, namely, the degree of control over molecular weight was nearly ideal (for certain conditions); and molecular weights could thus be predicted by simply following general rules relating to CRP mechanisms.

An experimental and modeling investigation of nitroxide-mediated radical polymerization (NMRP) of styrene using 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as controller is presented. The objective was to examine the effect of temperature, controller to initiator molar ratio, and initiation mode on conversion, molecular weight and polydispersity development, and also to generate a source of reliable experimental data for parameter estimation and further model validation purposes. Polymerizations with a bimolecular initiator (Benzoyl Peroxide; BPO) were carried out at 120 and 130°C, with TEMPO/BPO molar ratios of 0.9 to 1.5. The effects of temperature and TEMPO/BPO ratio on polydispersity, molecular weight averages and conversion (rate) were studied. Results indicate that increasing temperature increases the rate of polymerization while the decrease in molecular weights is only slight. It was also observed that increasing the ratio of TEMPO/BPO decreased both the rate of polymerization and molecular weights. To investigate the contribution of thermal self-initiation in NMRP of styrene, thermal NMRP of styrene with TEMPO in the absence of initiator was carried out at 120 and 130°C. The results were compared with regular thermal polymerization of styrene and NMRP of styrene in the presence of BPO. It was observed that although the thermal polymerization of styrene can be controlled to some extent in the presence of TEMPO to provide lower polydispersity polystyrene, the polymerization was never as controlled as that obtained by a BPO initiated NMRP. Additional experiments were conducted with a unimolecular initiator and compared to the corresponding bimolecular system with the same level of nitroxide at 120°C, to gain additional insight on the advantages and disadvantages of each system. In addition, the importance of diffusion-controlled (DC) effects on the bimolecular NMRP of styrene was assessed experimentally by creating conditions where DC effects may be present from the outset. The results were corroborated by mathematical modeling and it was concluded that DC-effects are weak in the NMRP of styrene, even in the presence of “worst case scenario” conditions created. Finally, a mathematical (mechanistic) model based on a detailed reaction mechanism for bimolecular NMRP of styrene was presented and the predicted profiles of monomer conversion, molecular weight averages and polydispersity were compared with experimental data. Comparisons suggest that the present understanding of the reaction system is still inconclusive, either because of inaccuracy in values of kinetic rate constants used or because of some possible side reactions taking place in the polymerization system that are not included in the model. This was somewhat surprising, given that papers on controlled radical polymerization, and NMRP in particular, have clearly dominated the scientific polymer literature in the last fifteen years or so.

This thesis presents the results of a study on the kinetics of nitroxide-mediated radical polymerization of styrene with a unimolecular initiator. The primary objective was to obtain a more comprehensive understanding of how a unimolecular-initiating system controls the polymerization process and to clarify the effects of various reaction parameters. Previous work in this field has met with some difficulties in the initiator synthesis, such as low yield and inconsistency of molecular weight. These problems were overcome by adjusting reaction conditions and procedures. Better yields of initiator with consistent molecular weight were produced by the improved methods. Control of polymerization rate and polymer molecular weight in unimolecular nitroxide-mediated radical polymerization was studied by looking at the effects of the three main factors: initiator concentration, temperature, and the initiator molecular weight on polymerization rate, molecular weight and polydispersity. Results indicated that increasing the initiator concentration had no effect on polymerization rate at low conversion, but led to lower polymerization rate at high conversion; higher initiator concentration led to lower molecular weight of the resulting polymer. It was also found that temperature significantly increased the polymerization rate, yet had no effect on number-average molecular weight, Mn, at low conversion, while it caused a plateau at high conversion levels; there was no effect on weight-average molecular weight, Mw, through the whole conversion range. In addition, increasing initiator molecular weight was found to have no effect on either polymerization rate or molecular weight. The experimental molecular weights of the unimolecular system were compared to theoretical molecular weights based on ideal controlled radical polymerization (CRP). The results were found to be close to the theoretical values. This confirmed the advantages of the unimolecular system, namely, the degree of control over molecular weight was nearly ideal (for certain conditions); and molecular weights could thus be predicted by simply following general rules relating to CRP mechanisms.

The peak and valley problems caused by oral administration, injection or other conventional methods, call for developing systems that can deliver therapeutics more effectively. As one of the techniques, diffusion-controlled drug release membranes have significant interest due to great ease with which they can be designed to achieve near-zeroth-order release kinetics. Since diffusion is the rate-limiting step in these systems, determining the permeability and diffusivity of drug molecules in the membrane is therefore important in evaluating drug release performance. This study focuses on the Membrane Permeation Controlled Release (MPC) system, which involves a non-porous (dense) membrane, comprising of two biopolymers, sericin and chitosan. Ciprofloxacin hydrochloride and (+)-cis-diltiazem hydrochloride were used as hydrophilic model drugs, and nitro-2-furaldehyde semicarbazone (Nitrofurazon) was used as a hydrophobic model drug. Permeation experiments were carried out in a semi-infinite reservoir/receptor system to simulate in-vitro drug release. The intrinsic permeability and diffusivity (P, D) of the drugs through the membranes were determined using a modified time-lag method based on short time permeation and mass balance method based on long time permeation. The partition coefficients Kd of the drugs in the membranes and the swelling degree of the membranes were determined by sorption/desorption experiments. The diffusivities of the drugs were also determined from the sorption/desorption kinetics. Over the experimental ranges tested, the drug concentration and membrane cross-linking did not have significant effects on these parameters presumably due to the relatively low drug concentrations and mild crosslinkings of the membranes. The diffusivity coefficients of ciprofloxacin hydrochloride, (+)-cis-diltiazem hydrochloride and nitrofurazon in the membranes were found to be in the range of (2.0-2.6)×〖10〗^(-9)±2.6×〖10〗^(-10) cm2/s, (2.5-2.6) ×〖10〗^(-9)±1.1×〖10〗^(-10) and (38-134) ×〖10〗^(-9)±33.1×〖10〗^(-9) (cm2/s), respectively, and their permeability coefficients were in the range of (24-29)×〖10〗^(-8),(51-52) ×〖10〗^(-8) and (131-169) ×〖10〗^(-8) (cm2/s), respectively. The partition coefficients were determined to be around 0.91±0.21, 25±0.12 and 26±0.31, respectively. The diffusivity coefficients determined from sorption experiments for ciprofloxacin hydrochloride, diltiazem hydrochloride and nitrofurazon were found to be in the range of (3.2-7.6) ×〖10〗^(-9)±6.3×〖10〗^(-8), (6-10) ×〖10〗^(-9)±2.6×〖10〗^(-8) and (15-18) ×〖10〗^(-9)±2.7×〖10〗^(-7) (cm2/s), respectively. Also the diffusivity coefficients determined from sorption experiments for ciprofloxacin hydrochloride, diltiazem hydrochloride and nitrofurazon were in the range of (20-47) ×〖10〗^(-9), (12-24) ×〖10〗^(-9) and (11-20) ×〖10〗^(-9) (cm2/s), respectively. Nonetheless the differences in the diffusivities calculated from permeation and sorption/desorption experiments are considered to be acceptable, in view of the different experimental techniques used in this work, for the purpose of comparison of the membrane diffusivity and permeability.

As individuals or families hold a substantial share of a firm at the cost of less diversified portfolio, they specialize their portfolio and have better inside information. Does the market marker react to this fact and maintain higher level of asymmetric information cost for such family-controlled firms? We analyze the bid-ask spread and the probability of informed trading (PIN) of Canadian-based publicly traded firms cross-listed with NYSE/AMEX to test this notion. We find that although the market maker maintains higher average spread, he does not form higher PIN for family-controlled firms when the entire day is considered as an event period. <p>The assumption of constant arrival rates of informed and uninformed traders during the day in Easley et al (1996b) is rejected in the two periods per day analysis. In addition, the notion of information event occurrence prior to the day in Easley et al (1996b) is consistently rejected as higher (non-statistically) probability of information events is found in the afternoon (second session) in the two (three) periods per day analyses, respectively. Based on these findings, we have serious doubts about any existing findings (including ours) of PIN based on one period per day. As such, we consider the possibility of several periods per day.<p>Though it remains an empirical question to choose how many periods should be considered, we find our results using two and three periods per day to be very interesting. We consistently reject the hypothesis that the PIN is higher for family-controlled firms. Since the market maker does not need to maintain high spread for firms with very high number of uninformed traders and very low number of informed traders, we do not perceive our findings to be either surprising or contradictory to the present literature. By developing a different formulation of PIN, we also show that this is empirically less than that developed by Easley et al (1996b).