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Thesis (MSc(Med)(Pharmacy) ) -- University of Limpopo, 2013. / Introduction: Primary Health Care (PHC) is regarded as the first level of contact with the National Health System with health care services provided mainly by nurses with varying competences. PHC is about interaction with people thus the quality of PHC depends extensively on the competence of the people who provide it. Therefore, the way health care personnel are trained and how capacity continues to be developed is of fundamental importance to PHC. Following the Alma-Ala Declaration, policies, such as the National Drug Policy (NDP) were developed in South Africa to guide health care services. The NDP resulted in the formulation of Standard Treatment Guidelines/Essential Medicine List (STGs/EML). Emphasis has been placed on all prescribers to strictly adhere to these guidelines when providing clinical patient care. Despite these developments reports still indicate that antibiotics are irrationally used when treating respiratory infections. It is therefore imperative that localised reasons for deviations from the STGs/EML when treating respiratory conditions are thoroughly investigated to facilitate relevant interventions. Objectives: The objectives of the study were to: (1) document the treatment prescribed to children up to 12 years of age for respiratory conditions, (2) assess adherence of the authorised prescribers to the 2008 PHC STGs/ EML and (3) determine factors impacting on deviations from the 2008 STGs/EML. Method: Twenty randomly selected PHC facilities in the district participated in the study. In each of the 20 selected PHC facilities, three prescribers were randomly selected for the structured interview and auditing of their prescription registers. Five prescriptions from each of the sampled prescription registers of the selected authorised prescribers, containing any of the children's respiratory conditions to be studied, were audited. A total of 15 prescriptions from each of the selected PHC facilities were audited. Descriptive statistics was used to xii analyse data and responses to categorical variables were summarised as frequency counts and percentages. Results were presented as tables, figures and graphs. Results: Pneumonia (39.7%) was found to be the most common respiratory condition seen at Umkhanyakude Health District followed by the common cold and influenza. Amoxicillin (52%) was the most often prescribed antibiotic for these respiratory conditions. Only 4% of prescribers showed full adherence to the 2008 PHC STGs/EML. While prescribers had a positive attitude towards the 2008 PHC STGs/EML, their sense of adherence, content understanding of these guidelines, as well as knowledge of medicine used for respiratory conditions, were exaggerated. Failure to accurately diagnose respiratory conditions and lack of implementation and monitoring strategies were also amongst the factors impacting on adherence. Conclusion: Adherence to the 2008 PHC STGs/EML for the treatment of respiratory conditions in children up to 12 years of age was found to be a challenge in Umkhanyakude PHC facilities with only four percent of prescribers adhering to these guidelines. The Umkhanyakude Health District Management team must consider employing multifaceted interventions from the recommendations of this study in order to improve adherence to the PHC STGs/EML. Recommendations: Strategies such as intensified monitoring and evaluation, improved supervision, targeted training and education together with compulsory in-service training are recommended to improve adherence to the STGs/EML in the Umkhanyakude Health District. Guideline implementation strategies with integrated approaches to guideline dissemination must also be strengthened.

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The Vasoactive Intestinal Peptide (VIP) is an agonist of the CFTR chloride channel in the human airways. In the genetic disease Cystic Fibrosis, where CFTR is defective or absent from the apical membrane of epithelial cells, VIP innervations are lost. Our group has demonstrated that VIP increases CFTR membrane stability through PKCε. However, the mechanism remained to be determined. Here we found that VIP stimulation increases the interaction of NHERF1 and P-ERMs with CFTR through PKCε phosphorylation. Moreover a reduction of the interaction between intracellular CFTR and the Golgi associated protein, CAL was observed following VIP stimulation. Silencing either ERMs or NHERF1 with siRNA prevented the VIP ability to increase CFTR surface expression and function, confirming that NHERF1 and P-ERMs are necessary for VIP regulation of the sustained activity of membrane CFTR. This study shows the cellular mechanism by which prolonged VIP stimulation of airway epithelial cells regulates CFTR-dependent secretions.

<p><strong>Abstract:</strong><strong> </strong></p> <p><em>Introduction:</em></p> <p>Because the relationship between pulmonary function and exercise tolerance is highly variable in COPD, other contributing factors were investigated. Physiological factors that contribute to exercise tolerance must contribute to the symptoms limiting exercise, thus the symptoms limiting exercise in COPD and their contributing factors were explored, including an investigation of novel mechanisms to explore the reported tiotropium bromide-mediated improvement in exercise tolerance in COPD.</p> <p><em>Methods:</em></p> <p>We conducted a retrospective, cross-sectional analysis of 4,424 COPD patients and 4,221 healthy subjects; referred to McMaster University Medical Center for exercise testing. Multiple linear regression, ridge regression, and MANOVA were utilized to determine the factors contributing to exercise tolerance, important symptoms limiting exercise, and factors contributing to dyspnea.</p> <p>A randomized, double-blind, placebo-controlled, crossover study of 20 COPD subjects was performed. Repeated measures ANOVA was utilized to determine effects of 3 weeks tiotropium bromide vs. 3 weeks placebo on cardiac output and efficiency of gas exchange during exercise.</p> <p><em> </em></p> <p><em>Results:</em></p> <p>MBC, DL_CO, and quadriceps strength were the three major, independent, contributors to exercise capacity (MPO = -206.3 + 5.1*Quadriceps Strength + 1.8*MBC + 10.0*DL_CO, r² = 0.677). MANOVA further illustrated this.</p> <p>Dyspnea, alone or in equal combination with leg effort, was the most important symptom limiting exercise in COPD. V_E and MBC were the two major, independent, contributors to dyspnea (Dyspnea = 0.95 + 0.08*V_E + -0.01*MBC, r² = 0.457). The increase in dyspnea with V_E was much greater than the decrease with MBC.</p> <p>Tiotropium bromide did not significantly (p = 0.72) improve the efficiency of gas exchange for oxygen, significantly worsened (p = 0.005) the efficiency of gas exchange for carbon dioxide, and did not improve cardiac output.</p> <p><em>Conclusion:</em></p> <p>We concluded the reported tiotropium bromide-mediated improvement in exercise tolerance in COPD is not mediated through improvements in gas exchange efficiency and/or cardiac output.</p> <p><strong><br /></strong></p> / Doctor of Philosophy (Medical Science)