This thesis presents results of a case-control study investigating the excess risk of ocular hypertension or open-angle glaucoma associated with the use of oral, inhaled and nasal glucocorticoids. Data on 9,793 cases and 38,325 control subjects were obtained from the computerized administrative health databases of the province of Quebec, Canada. / For oral glucocorticoids, a 40% increase in the risk of ocular hypertension or open-angle glaucoma was observed. The risk increased with higher daily doses and increasing duration of treatment. / Exposure to inhaled glucocorticoids was not associated with an elevated risk, except when they were administered in high doses over extended periods of time. No elevated risk was observed for exposure to nasal glucocorticoids. / The study results are discussed in view of pharmacological data for different forms of glucocorticoids and compared to findings for ophthalmic glucocorticoids. The database is used to illustrate empirical explorations of concerns about bias.

Objective. To evaluate the clinical effectiveness of a community pharmacy based education program for asthma patients. / Design. A randomized controlled trial was conducted in 16 community pharmacies. Interventions: Patients in the intervention group (n=53) received three sessions of individualized asthma education from pharmacists. In addition, pharmacists also prepared a written action plan in consultation with patients' physicians. Patients in the control group (n=53) did not receive any asthma education during the study. / Outcome Measures. Asthma symptoms (the primary outcome), asthma knowledge, medication compliance, deep expiratory pressure percentage (DEP%), inhaler technique, quality of life (QOL), and heath resources utilization were measured. / Results. The mean score of asthma symptoms, the primary outcome, decreased more in the intervention group than in the control group (between group difference = -0.299, 95% CI, -0.71; 0.11), though this between group difference was not statistically significant (P=0.148). As to the secondary outcomes, patients in the intervention group had significant improvements in "overall mean score of QOL" (between group difference = 0.43, 95% CI, 0.023; 0.83), "symptom domain of QOL" (between group difference = 0.50, 95% CI, 0.04; 0.96), and "inhaler technique of Aerosol-dosing only" (between group difference = 1.77, 95% CI, 0.36; 3.18). Except for QOL and inhaler technique, the other four secondary outcomes did not achieve any significant differences between the two study groups. / Conclusions. Most of the study results were not statistically significant. One important reason for this was the lack of power due to the poor success in patient recruitment. The study also highlighted some of the limitations and difficulties in implementing a community pharmacy based asthma education program. Despite these difficulties, some benefits were found. Therefore, we suggest that future studies should focus on overcoming the limitations and difficulties observed in this study.

Physicians have traditionally withheld opioid analgesics from patients with acute abdominal pain due to concerns of masking physical findings. No study has examined morbidity and mortality after narcotic administration. The purpose of this study was to determine: (1) frequency of abdominal pain requiring narcotic analgesics, and (2) rate of serious outcomes, (death, infection, perforation, obstruction or hemorrhage of abdominal organs), in order to assess the feasibility of a randomized clinical trial on the safety of narcotics. Of 860 patients with acute abdominal pain, 477 (55%) completed a pain questionnaire, and 321 met study criteria for need of narcotic analgesia (37.3%). Of these, 36 (11.2%) experienced a serious outcome as assessed by telephone contact 2 to 3 weeks after initial visit. The overall rate of serious outcomes was 67 of 860 (7.8%). A clinical trial using serious outcomes as the primary endpoint is possible, but would need to randomize approximately 3200 patients.

We used a mailed questionnaire to investigate over-the-counter (OTC) analgesic medication use. The response rate was 77% (n= 1.339). 79% of women and 64% of men had consumed OTC analgesics in the past month, mostly on only 1-3 days, but 6% of users took them every day or almost every day. The most common reason for use was headache, followed by back and joint pain. 5% used larger doses than recommended. Women took more analgesics, but reported suffering more problems: gender differences disappeared when the number of problems was controlled. Remembered mood before and after medication indicated a substantial improvement in mood that was only partially explained by pain relief. This may explain the 81 cases who reported taking OTC analgesics for fatigue, stress, etc. Health practitioners need to determine if OTC analgesic use is appropriate and pain relief is adequate. Effects of OTC analgesics on mood need to be further investigated.

This thesis describes the preparation, characterization and biological study of block copolymer aggregates as drug delivery vehicles. A novel method is described for the synthesis of biodegradable and biocompatible copolymers of polycaprolactone-b-poly(ethylene oxide). The copolymers and their aggregates are then characterized with special attention given to properties which are of most interest to applications in drug delivery such as copolymer composition, thermal behavior, critical water content, critical micelle concentration, partition coefficient of hydrophobic solubilizates, morphology of the aggregates and in vitro biocompatibility. The polycaprolactone-b-poly(ethylene oxide) copolymer micelles are first explored as a delivery vehicle for the neurotrophic agents FK506 and L-658,818. The in vitro delivery and biological activity of the micelle-incorporated drugs are confirmed in PC12 cell cultures. The in vivo biological distribution of the micelle-incorporated FK506 was assessed in Sprague Dawley rats both 6 and 24 hours following intravenous administration. Also, the biological activity of the micelle-incorporated FK506 was shown to be retained in vivo using the sciatic nerve crush model of peripheral neuropathy in Hanover Wistar rats. The question of whether or not the cellular internalization of the polycaprolactone- b-poly(ethylene oxide) micelles proceeds by an endocytotic mechanism is addressed in PC12 cell cultures. Finally, the polycaprolactone- b-poly(ethylene oxide) micelles are explored as a delivery vehicle for dihydrotestosterone. We report on several of the physico-chemical characteristics of the micelle-incorporated dihydrotestosterone as well as in vitro delivery in HeLa cells which have been cotransfected with the MMTV-LUC reporter gene and the androgen receptor.

<p> Bioresponsive hydrogels are emerging with technological significance in targeted drug delivery, biosensors and regenerative medicine. The design challenge is to effectively link the conferred biospecificity with an engineered response tailored to the needs of a particular application. Moreover, the fundamental phenomena governing the response must support an appropriate dynamic range, limit of detection and the potential for feedback control. The design of these systems is inherently complicated due to the high interdependency of the governing phenomena that guide sensing, transduction and actuation of the hydrogel. The objective of the dissertation is to review the current state of bioresponsive hydrogel technology and introduce a method of extending the technology through integrated control loops; explore fundamental phenomena which affect ion transport within biomimetic hydrogels; and investigate, via <i> in silico</i> studies, the fundamental design parameters for the implementation of a feedback control loop within a bioresponsive hydrogel. </p><p> In one study, effects of valence number, temperature and polymer swelling on release profiles of monovalent potassium and divalent calcium ions elucidates mechanistic characteristics of polymer interactions with charged species. For comparison, ions were loaded during hydrogel formulation or loaded by partitioning following construct synthesis. Using the Korsmeyer-Peppas release model, the diffusional exponents were found to be Fickian for pre- and post-loaded potassium ions while preloaded calcium ions followed an anomalous behavior and postloaded calcium ions followed Case II behavior. Results indicate divalent cations interact through cation-polyelectrolyte anion complexation while monovalent ions do not interact with the polymer. Temperature dependence of potassium ion release was shown to follow an Arrhenius relation and calcium ion release was temperature independent. </p><p> In another study, data generated from the previous Chymotrypsin system is used to build and validate a finite element model. The model provides insight into key engineering parameters for the design of an enzymatically actuated, feedback controlled release. A drug delivery platform comprising a biocompatible, bioresponsive hydrogel and possessing a covalently tethered peptide-inhibitor conjugate was engineered to achieve stasis, via a closed control loop, of the external biochemical activity of the actuating enzyme. The FEM model was used to investigate the release of a competitive protease inhibitor, MAG283, via cleavage of Acetyl-Pro-Leu-Gly|Leu-MAG-283 by MMP-9 in order to achieve targeted homeostasis of MMP-9 activity, a goal for the treatment of chronic wound pathophysiology. It was found the key engineering parameters for the delivery device are the radii of the hydrogel microspheres and the concentration of the peptide-inhibitor conjugate loaded into the hydrogel. </p><p> Homeostatic drug delivery, where the focus turns away from the drug release rate and turns towards achieving targeted control of biochemical activity within a biochemical pathway, is an emerging approach in drug delivery methodologies for which the potential has not yet been fully realized. By understanding mechanistic phenomena and key engineering parameters for design, advancements in bioresponsive hydrogels will continue to produce novel technologies in biomedical applications.</p>

<p><b>Problem</b>: Fear of a painful dental injection and subsequent avoidance behavior are significant barriers to regular visits to the dentist. An anesthetic procedure that would avoid the discomfort of a local anesthetic injection thus obviating fear and anxiety about receiving a &ldquo;shot,&rdquo; would greatly benefit dental patients. </p><p> <b>Methods</b>: The study employed a multi-center, randomized, double-blind, placebo-controlled, parallel-groups design to assess the safety and efficacy of Kovacaine Mist delivered intranasally for inducing pulpal anesthesia of maxillary teeth sufficient to allow completion of the Study Dental Procedure. A total of 36 subjects, randomized 2:1 (Kovacaine Mist: Placebo) were enrolled. </p><p> <b>Results</b>: Kovacaine Mist was significantly superior to placebo (p&lt;0.0001) with respect to the proportion of subjects who did not require rescue by injection of local anesthetic to complete the Study Dental Procedure. </p><p> <b>Conclusions</b>: Based of the results of this clinical trial, a nasal anesthetic, such as kovacaine mist, could potentially be used as a safe and effective alternative to maxillary infiltration for anesthetizing maxillary premolars and anteriors to achieve pulpal anesthesia. </p>

<p> There is a growing interest in exploring the emotional intelligence (EI) of pharmacy leaders. The purpose of this research was to explore the differences between leadership-certified and non-leadership-certified pharmacy leaders and their Total emotional quotient (EQ) score, as measured by the Emotional Quotient Inventory (EQ-i 2.0&reg;). A secondary purpose was to identify if there was a difference between leadership-certified and non-leadership-certified pharmacy leaders and their EI scores with regard to the EQ-i 2.0&reg; composite scales (Self-Perception, Self-Expression, Interpersonal, Decision Making, and Stress Management). In addition, the relationship between demographic features of pharmacy leaders and Total EQ scores was evaluated. A quantitative, non-experimental design using secondary data was used to measure EI in a stratified random sample of pharmacy leaders, including 2008-2012 graduates and 2013 participants of the American Society for Health System Pharmacy (ASHP) Foundation Pharmacy Leadership Academy (PLA). The results revealed a mean Total EQ score of 101.11, indicating an average level of EI function among pharmacy leaders. Leadership-certified pharmacy leaders had statistically significantly higher Total EQ scores than non-leadership-certified pharmacy leaders. Furthermore, leadership-certified pharmacy leaders scored significantly higher than non-leadership-certified pharmacy leaders on all five composite scales of EI. No demographic factors were significant predictors of Total EI score of pharmacy leaders. The results indicate graduates of the ASHP PLA had higher EI than current participants of the PLA, but there is a need for continued leadership and EI training for all pharmacy leaders across all areas of EI function.</p>

Microencapsulation of the enzyme phenylalanine ammonia-lyase (PAL) was developed for in vivo depletion of systemic phenylalanine (PHE) in Phenylketonuric (PKU) rats. Phenylalanine ammonia-lyase was successfully microencapsulated within artificial cells. The immobilized enzyme had an assayed activity of 20% $ pm$ 4% (Mean $ pm$ S.D.) of the free enzyme in solution. The immobilized enzyme maintained a higher enzyme activity at very low pH compared to the free enzyme in solution. The pH optimum of the free and immobilized enzyme was 8.5. This pH optimum corresponds to the average pH range of the small intestine. / PKU induced rats had a 10 to 20-fold increase in the amino acid phenylalanine in the systemic circulation. This amino acid elevation was comparable to the plasma phenylalanine increase in human PKU patients. Daily oral administration of artificial cells containing 5 units of the enzyme PAL, to PKU rats, lowered on an average the systemic phenylalanine level to 20% $ pm$ 8% (Mean $ pm$ S.D.) of the original levels in 7 days (P $<$ 0.001). After 7 days of this form of enzyme therapy, systemic blood phenylalanine levels of PKU treated rats were lowered to levels not significantly different from those of normal rats. Unlike control PKU rats, the treated group showed no signs of abnormal behavior or weight loss. / HPLC analysis of free amino acids in the plasma, cerebro-spinal fluid and brain of PKU rats was carried out in the following groups: (1) Normal rats, (2) PKU rats on a normal diet, (3) PKU rats on a high phenylalanine diet, (4) PKU rats on a phenylalanine free diet, and (5) PKU treated rats with PAL-loaded artificial cells. Amino acid compartmental distribution was different in all these groups. / The oral administration of PAL-loaded artificial cells decreased the hyperphenylalaninemia in all the compartments studied. It also corrected the imbalance of many amino acids, including tyrosine and tryptophan, in the CSF and the brain. This enzyme therapy was more effective in compartmental PHE level depletion, than a PHE-free diet.

The association between side effects to antimalarial chemoprophylaxis and noncompliance was assessed in travellers visiting five pre-travel clinics in the greater Montreal area between February and August 1996. Participants completed pre and post-travel questionnaires to ascertain frequency and severity of side effects and compliance with malaria chemoprophylaxis. A participation rate of 83% was achieved. Of 157 travellers prescribed mefloquine and 132 travellers prescribed chloroquine, proportions experiencing symptoms or side effects were high (7% and 83%, respectively), but not statistically significantly different. Gastrointestinal side effects were more common in chloroquine users (68%) than in mefloquine users (56%) (p = 0.04). No difference was observed in proportions of psychological side effects between groups; however, they were more commonly reported in the mefloquine group. Between 26% and 33% of noncompliance was directly attributed to side effects; however, logistic regression analysis showed no significant impact of side effects on noncompliance, after controlling for other determinants.