Chronic neuropathic pain is a disease that impacts the livelihood of millions of people in the United States with no effective pain treatments and limited information pertaining to the underlying mechanisms. Opioid therapy is considered the gold standard for pain therapeutics, but chronic use of these medications brings about serious side effects such as tolerance, addiction, and respiratory depression which limit their overall therapeutic potential. Herein, two approaches are discussed to circumvent these issues: i) a multifunctional approach using N-phenyl-N-piperidin-4-yl-propionamide (Ppp) coupled to various endogenous opioid ligand scaffolds, and ii) non-opioid dynorphin A (DYN A) ligands at the Bradykinin-2 receptor (B2R). The μ-opioid receptor (MOR) upon agonist stimulation provides analgesia and concomitant activation of the δ-opioid receptor (DOR) leads to an increased antinociceptive effect. Chronic activation of the MOR has been correlated with an upregulation of the κ-opioid receptor (KOR) and KOR associated side effects such as anxiety and depression. The discovery of a new class of opioid receptor (OR) ligands that have the biological profile of MOR/DOR agonists and KOR antagonists would be beneficial considering they would have an increased analgesic effect, leading to a lower dosage being administered and thus lower overall side effects, and block symptoms elicited from KOR stimulation. Discussed are various structure activity relationships (SARs) of numerous scaffolds that present novel biological profiles. Ultimately, we discovered a compound that, to our knowledge, is the 1st MOR/DOR agonist and KOR antagonist. DYN A is the endogenous ligand for the KOR and its [des-Tyr1]-DYN A fragment interacts with the B2R, but not the KOR, promoting hyperalgesia. Peptidomimetic non-opioid DYN A analogues were synthesized and evaluated at the B2R. A minimum pharmacophore was identified and antagonists with both improved biological stability and affinity were discovered.

Chronic kidney disease (CKD) is an important independent risk factor in the development of cardiovascular disease (CVD). Indeed, patients with CKD are far more likely to die from CVD than reach end stage renal disease. Conventional cardiovascular risk factors and co-morbidity contribute to this increased risk of CVD. However, emerging evidence suggests other novel factors including inflammation, oxidative stress, and a shift in the balance of the vasodilator nitric oxide and vasoconstrictor endothelin system, are also important contributors. Despite increasing evidence that the endothelin system plays an important role in the development of CKD and CVD, there has been little research examining possible therapeutic benefits of its modification in patients with CKD. The overall aims of the work presented within this thesis were to examine CVD risk in patients with renal impairment and then to see what impact chronic inhibition of the endothelin system would have on risk factors for CVD and CKD progression. In the first two studies I examined markers of arterial stiffness (AS) and endothelial function in a cohort of patients with immune-mediated renal disease. I was able to show in the acute setting that improvement in renal function following treatment for these conditions leads to significant improvements in AS. Interestingly, in patients who were in remission from their renal disease, only classical cardiovascular risk factors appear to be linked to AS. In the next study I was able to prove that sitaxsentan, a selective oral ETA antagonist, did not cause functional blockade of the ETB receptor in man. This was the first study of its kind to confirm that a “selective” endothelin antagonist truly is selective in vivo: a finding that will allow more accurate mechanistic investigation of the ET system. In the final studies, I showed that in subjects with stable non-diabetic proteinuric CKD, chronic selective ETA receptor antagonism reduces blood pressure and AS, and that these systemic benefits are associated with an increase in renal blood flow and reduction in proteinuria. The reduction in proteinuria is most likely haemodynamic and linked to a fall in GFR and filtration fraction, similar to what is seen with ACE inhibitors. Importantly, these benefits were seen in patients already taking maximally tolerated renin-angiotensin aldosterone system blockade, suggesting that chronic endothelin antagonism could be an important future therapy in the management of CKD. In summary, I have shown that renal impairment can directly affect markers of arterial function and by inference increase the risk of CVD. Chronic antagonism of the endothelin system with ETA receptor blockers would appear to improve many of these biomarkers, including reductions in BP, AS and proteinuria. There were no adverse effects reported in these studies, suggesting that selective ETA antagonism may be safe enough for clinical development in CKD patients. Further larger clinical trials are warranted.

Class of 2016 Abstract / Objectives: To describe the patterns of benzodiazepine use at a community health center in adults and to identify common demographic factors and chronic conditions that are associated with an increased usage rate. Subjects: Patients 18 years and older who had been treated at El Rio Community Health Center with an active benzodiazepine prescription on file. Methods: Data were collected from patient charts using a data collection form. Assessment included current benzodiazepine patients were taking, concurrent use of opiates and/or antispasmotics, indication for benzodiazepine use, concurrent medications for anxiety, depression, or insomnia, and prescriber type. Demographic data on age, gender, race, ethnicity, insurance type, and use of tobacco or alcohol were also collected. Results: Data were collected on 102 patients currently taking a benzodiazepine; 60 patients (mean age = 61.2, SD = 13.6) had concurrent first-line therapy for anxiety, depression, or insomnia and 42 patients (mean = 61.1, SD = 13.6) did not. There were a significantly higher proportion of women taking a benzodiazepine with first-line therapy than without first-line therapy (88.3% vs. 71.4%; p = 0.031). Additionally, higher proportion of benzodiazepine was prescribed with first-line therapy for depression than other indications (p = 0.002). Conclusions: More patients were prescribed benzodiazepines with concurrent first-line therapy for depression than other indications such as anxiety, insomnia, or other panic disorders. For this reason, health care professionals should be aware of the patterns of benzodiazepine use and comply with current recommended practice guidelines.

Doctor of Philosophy / School of Family Studies and Human Services / Jared A. Durtschi / Despite previous literature illustrating strong links between social relations, mental health, and health outcomes, much remains unknown regarding the associations among adult romantic attachment, depression, and reports of physical health within those diagnosed with a chronic disease. Using a sample of 197 individuals who reported a diagnosed chronic disease and in a cohabiting or romantic relationship from the Flourishing Families Project, a mediated latent growth curve analysis was used to test to what extent trajectories of reported physical health across two years were a function of attachment and depression. Specifically, trajectories of physical health were modeled to examine changes over two years with time-invariant covariates of depressive symptoms and adult attachment predicting initial levels of physical health and changes in physical health over time. Results indicated that as depressive symptoms increased, initial levels of physical health were worse. Higher reports of attachment anxiety were linked with better initial reports of physical health. Further, higher reports of depressive symptoms and attachment anxiety predicted a significant upward shift in the expected trajectory of improved physical health. These results expand current research and theory by examining how adult attachment and depression are linked with expected trajectories in physical health over time.

Magister Public Health - MPH / This study determined the affordability of medicines for diabetic patients attending the diabetic clinic of the University of Nigeria Teaching Hospital (UNTH), Enugu. The Study was a cross-sectional time-delimited, descriptive study of affordability of Medicines for diabetic patients aged >18 year s 18 years and who pay for medicines out of pocket. A structured questionnaire was used to collect sociodemographic information about patients and the prescription was assessed in terms of conformity with essential medicines list (EML), cost and ability to be completely filled by the patient. Data was analysed using EPI Info software.the results show that medicines prescribed for diabetes are unaffordable to the majority of patients who attend the UNTH diabetic clinic. / South Africa

Class of 2011 Abstract / OBJECTIVES: The purpose of this study was to survey prescribers who manage patients with chronic pain to evaluate how pharmacy services are perceived to affect patients’ quality of life. METHODS: Surveys were sent to prescribers who manage patients with chronic pain. Prescribers rated pharmacy services on a scale of 0 – 5 (0 being not important at all, and 5 being extremely important) to the quality of life of patients with chronic pain. RESULTS: Surveys were completed by 23 subjects. Prescribers ranked pharmacy services as follows: the pharmacy fills opioid prescriptions for all pain conditions (mean = 4.2; SD = 1.0), the patient is able to obtain the entire quantity of pain medication (mean = 4.1; SD = 1.5), the pharmacy treats the patient as dependent on, not addicted to opioids (mean = 3.9; SD = 1.6), the pharmacy collaborates with the prescriber to manage opiate therapy (mean = 3.9; SD = 1.5), the pharmacy stocks new and recently approved pain medications (mean = 3.8; SD = 1.1), the pharmacy provides the patient with information on adverse effects of pain medications (mean = 3.8; SD = 1.5), the pharmacy is able to use manufacturer co-pay cards to minimize out-of-pocket costs (mean = 3.5; SD = 1.7), the patient can have prescriptions delivered to their home (mean = 2.1; SD = 1.8) and the patient can obtain a prescription without having to wait a specified time period determined by their pharmacy (mean = 1.8; SD = 1.5). CONCLUSION: Prescribers in this study felt that certain pharmacy services are very important in the treatment of patients with chronic pain. Pharmacies may improve patients’ quality of life in the management of their chronic pain by providing these services.

Class of 2012 Abstract / Specific Aims: The objectives of this study were to determine the financial impact and mortality of CLL and Richter’s transformation in CLL in the inpatient setting in the payer’s perspective, the common diagnoses at discharge for patients with CLL, and to compare demographics, hospital characteristics, and co-morbidities for CLL cases versus Richter’s only cases. Methods: This study was a retrospective cohort of inpatient hospital charges and mortality of CLL patients and CLL patients with Richter’s transformation in the United States in the perspective of the payer. Using weighted statistical methods, results of this investigation yielded nationally-representative findings. The hospital charges were analyzed with a gamma regression with log link, and mortality was analyzed with a generalized linear regression. Main Results: There were total of 391,287 cases and 7% (27,259) were Richter’s cases. The overall hospital charges for CLL and CLL patients with Richter’s transformation from 2005 to 2009 were $38,735 (±58859) per case and $53,118 (±77993) per case, respectively. The mortality was 6.3% (24,520 deaths) overall and 9.1% mortality (2,485 deaths) for Richter’s transformation patients. The significant predictors (p < 0.05) that were associated with an increase the hospital charges for Richter’s patients was sepsis while sepsis and weight loss were associated with an increase in mortality. Conclusions This study adds to the few studies published to show the impact of CLL and Richter’s. However, due to the limitation on pharmacotherapies, it was not possible to determine therapeutic cost drivers for these cases. Future studies are warranted to determine the cost of therapies associated to the different stages of CLL.

The “two-hit” schizophrenia hypothesis suggests genetic and environmental abnormalities interrupt early CNS function. This increases vulnerability of a “second hit” and schizophrenia onset. Chronic stress and decreased Reelin signaling are reportedly associated with schizophrenia. Heterozygous Reeler Mice (HRM) show a 50% reduction in Reelin and display major schizophrenia phenotypes. Receptor-Associated Protein (RAP) blocks ligand-association to Reelin receptor Apolipoprotein E receptor 2 (ApoER2). In this study, we sought to replicate major heterozygous reeler mouse (HRM) phenotypes using in vivo RAP studies to establish an experimental in vitro model. Using an in vitro model, we investigated the effects of chronic stress and decreased Reelin signaling on AMPAR subunit expression. Implantable Alzet osmotic pumps allowed bilateral ventricular 7nM RAP perfusion in 12-14 week-old mice. An assay revealed significant Dab-1 phosphorylation reduction in RAP-perfused animals. These results correspond with learning and memory and associative-fear conditioning abnormalities. Overall activity, sensory perception, and nociception remained unaltered. RAP-perfused mice displayed deficits in pre-pulse inhibition to acoustic startle, and therefore sensory-gating deficits. A significant decrease in Glur1 and Glur2/3 expression was observed in primary hippocampal/cortical neurons following chronic RAP and CORT exposure. Collectively, our results show postnatal Reelin signaling disruption produces physiological, biochemical, and behavioral phenotypes similar to the HRM model. The exact mechanism of Reelin-dependent AMPAR insertion remains unclear. Glur1 and Glur2/3 appear to be inserted by differing mechanisms. Glur1 is reported to be inserted with Reelin activation of phosphoinositol-3-kinase (PI3K) signaling. Glur2/3, whose mechanism of insertion is unknown, has not been shown to be inserted via PI3K. Our findings also demonstrate the usefulness of in vitro RAP use, in which apolipoprotein E receptor 2 (ApoER2) expression is predominant compared to other lipoprotein receptors that may be affected with RAP application.

Background: Patients with chronic neck pain have a number of factors that could constitute a predisposition for respiratory dysfunction. However, the existing evidence is limited and not well established, and many questions such as the association of neck pain deficits with respiratory function remain unanswered. Thus, the aim of this study was to investigate whether patients with chronic neck have accompanying respiratory dysfunction and which are the neck pain deficits which principally predispose to these respiratory disturbances.Methods: In this case-control observational study, 45 patients with chronic idiopathic neck pain (>6 months, at least once per week) and 45 healthy age-, gender-, height- and weight-matched controls were voluntarily recruited. A third group of 10 patients with chronic non-spinal musculoskeletal pain was also used, but only for future reference. Participants' neck muscle strength and endurance were measured by an isometric neck dynamometer and craniocervical flexion test respectively. Range of movement was assessed by using an ultrasound-based motion analysis system. Forward head posture was assessed by obtaining lateral photographs and calculating the craniovertebral angle. Disability and neck pain intensity were assessed through the Neck Disability Index and Visual Analogue Scale. Psychological assessment was performed by using the Hospital Anxiety and Depression Scale, the Pain Catastrophizing Scale and the Tampa Scale for Kinesiophobia. Spirometry was used for assessing pulmonary volumes, flows and maximal voluntary ventilation. Respiratory muscle strength was assessed by using a mouth pressure meter. Finally, PaCO2 was assessed by using transcutaneous blood gas monitoring.Results: Patients with chronic neck pain were found to have weaker respiratory muscles than healthy controls (p<0.05). Their pulmonary volumes and maximal voluntary ventilation were also found to be reduced (p<0.05). Their mean respiratory flows were found to be unaffected (p>0.05), whereas their peak flows were reduced (p<0.05). Their partial pressure of carbon dioxide was also found to be affected (p<0.05), revealing existence of hypocapnia (PaCO2<35mmHg). The neck pain deficits that were found to be mostly correlated with these respiratory parameters were the neck muscle strength, neck muscle endurance, kinesiophobia, catastrophizing and pain intensity (r>0.3, p<0.05). Finally, the regression models revealed that neck pain deficits and especially neck muscle strength can provide a quite generalizable accurate estimation of this respiratory dysfunction (R2=0.28-0.52).Conclusions: Patients with chronic neck pain present dysfunction of their respiratory system which can be mainly manifested as respiratory weakness and/or hypocapnia. Pain intensity, neck muscle weakness, fatigue and kinesiophobia seem to be the most important deficits predisposing to this respiratory dysfunction. The understanding of this dysfunction could have a great impact on various clinical aspects notably patient assessment, rehabilitation and drug prescription. However, further research is suggested mainly directed towards optimizing treatment protocols and developing classification systems improving clinical reasoning.

Background: Chronic obstructive pulmonary disease (COPD) is a devastating illness that affects 4.3% of the population of British Columbia over the age of 45 years. Asthma is known to coexist in 10-20% of individuals with obstructive lung disease, and adds to the substantial burden of illness posed by COPD alone. Inhaled corticosteroids (ICS) are currently recommended for the management of COPD among individuals with frequent exacerbations; however, the ability of inhaled corticosteroids to reduce death and hospitalizations among individuals with COPD is controversial. Less is known about the effectiveness of ICS among individuals who are afflicted with both COPD and asthma. Methods: We used a retrospective cohort study design and administrative data to estimate the relative effectiveness of ICS in reducing hospitalizations or death among individuals with concomitant asthma and COPD, compared with individuals with COPD alone. We used an extended Cox model to estimate this association, with a time-varying measure of exposure to ICS. Results: We did not find any association between ICS and hazard of death or hospitalization among individuals with COPD alone (HR = 0.99; 95% CI: 0.94 – 1.05), however the hazard was 18% lower (HR = 0.82; 95% CI: 0.69-0.99) among individuals with concomitant disease. Conclusions: Individuals with combined COPD and asthma show significant benefit from the use of ICS and are more responsive to the effects of ICS than individuals with COPD alone. / Medicine, Faculty of / Population and Public Health (SPPH), School of / Graduate