A dissertation submitted to the Faculty of Health Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in medicine. Johannesburg 2014 / Introduction: The presence of pain during sleep causes patients with chronic daily pain, such as in Rheumatoid and Osteoarthritis, to experience insomnia, fragmented sleep and an increased number of night-time awakenings. This poor sleep results in an increased sensitivity to pain during the day. The effect of improving sleep on pain, sleep and mood after taking Zolpidem MR was the aim of this study. Methods: 11 patients from Chris Hani Baragwanath Hospital in Soweto South Africa who reported insomnia and daily pain spent 4 weeks in this crossover design, double blinded, placebo controlled study. Week 1- baseline, week 2 and 4 were Intervention weeks – either placebo or Zolpidem MR, week 3 was a Washout week. Data collected included actigraphy, McGill Pain Questionnaire, PSQI, BDI, physical activity questionnaire and daily sleep and pain diaries containing VAS scales for sleep and pain. Results: No significant changes were found in the pain or physical activity levels in any of the patients. Sleep quality, as measured by an isolated PSQI question, was improved by Zolpidem MR (p=0.0075). PSQI was decreased in the final week of the study compared to baseline (8.7 vs. 11.3, p=0.0106) and BDI was lower in week 4 than baseline (7.7 vs. 15.85, p=0.0003), BDI was also lower in week 4 compared to week 2 (7.7 vs. 12.8, p<0.05). However the changes in PSQI and BDI were a result of the order of the weeks, with patients interacting with the researcher and were not due to either Zolpidem MR or placebo. Anecdotal reports include feeling more energised and capable of living life. Conclusion: This study has shown that human interaction is an important component of treatment for insomnia and chronic pain as there is a positive effect on sleep disruption and depression.

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A study into the applicability of laser ablation inductively coupled plasma-mass spectrometry (LA ICP-MS) coupled with native polyacrylamide gel electrophoresis (PAGE) to metal speciation in proteins is described in this thesis. Chapter one of the thesis outlines the various roles played by metal ions in clinical samples. Health risks can arise from anthropogenic metal enrichment and metallodrug therapy is identified as a key source. The use of platinum and gold metallodrugs is discussed in detail. Speciation of metals in clinical samples is examined, concentrating on some of the techniques currently employed and their limitations. Particular attention is paid to the techniques employed in the study. The aim of the study is outlined - to develop an alternative speciation strategy for the study of metals in proteins. The reagents and instrumentation used are described in chapter two along with all experimental procedures. Chapter three describes the method development and determination of the analytical performance of the technique. The technique is used to study platinum speciation of protein samples enriched in vitro, the metal distribution profiles obtained are shown. The technique is next applied to the analysis of in vivo samples obtained from platinum therapy patients and a control source. Chapter four outlines the application of the technique to analysis of gold enriched samples both in vitro and in vivo from chrysotherapy patients. The gold distribution profiles obtained are shown and discussed. Chapter five looks at multi-element distribution and interactions occurring in serum. Elements naturally occurring at trace levels in serum, such as Cu and Fe, are studied in vivo. Other, lower level metals are studied following in vitro enrichment. Chapter six concludes the study. It discusses how the technique was found to be applicable for metal speciation of clinical samples by meeting the criteria laid out at the start of the study. Recommendations for future work are also outlined.

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Chronic pain may be defined as pain which persists in a patient for a prolonged period of time. Although this period of time may range from 3-12 months, it is most commonly described as pain which extends beyond the time required for healing. Chronic pain may also be classified into two different categories depending on the cause. The first category is nociceptive, which is chronic pain caused by activation of nociceptors. This may be due to several factors such as trauma or temperature. The second category is neuropathic chronic pain. These are chronic pains which are not necessarily caused by trauma, but more likely due to the malfunction of the nervous system. For this study, our aim is to develop a patient-controlled, externally actuated hydrogel system which is capable of ‘ON-OFF’ drug release. The model drug which was incorporated into the SAPD was a Non- Steroidal Anti-Inflammatory Drugs (NSAID), and thus our drug release system would be beneficial primarily for nociceptive chronic pain. This subcutaneously implanted SAPD is produced with an electroactive polymer which allows drug release in the presence of electrical stimulation. This would result in direct availability of drug at the site of actuation with reduced side-effects and increased drug bio-availability. The SAPD was formed by crosslinking polyvinyl alcohol (PVA) with diethyl acetamidomalate (DAA). The result was a hydrogel which was capable of swelling while remaining insoluble when placed in various solvents. After the hydrogel was synthesized, indomethacin was incorporated as the model drug. Indomethacin exhibited superior Drug Entrapment Efficiency (DEE) (±70-90%) and responsive release in the presence of an electrical stimulus. Finally, polyaniline (PANi) was used as the electroactive polymer in order to enhance the conductivity and allow sufficient release of the drug. Optimization of the SAPD was undertaken with a 3-factor Box-Behnken Design which measured the rate of erosion, drug release and DEE. The optimized SAPD was synthesized using PVA (0.8g) crosslinked with DAA (0.0689g) and a concentration of 1.3418%w/w PANi. Indomethacin was used and the DEE achieved was 76.32±10.46% (target 80.5381%). The drug release profile was 1.622%±0.1857% (target 1.7%) per release cycle and erosion rate was 5.73±1.26% (target 6.3201%) when actuated with a potential difference of 1V for a duration of 1 minute. Chemometric modelling performed on the SAPD showed that drug release may be attributed to erosion of the SAPD in the presence of an electrical stimulus. The polymeric strands usually rest as a coiled state within the SAPD. This coiled state may be the reason the hydrogel remained intact in the absence of electrical stimulation. However, external electrical fields may adduct to form a coil rather than an extended chain resulting in the formation of a globular aniline-vinyl complex. This formation thus leads to a weakened form of the hydrogel structure, resulting in breakdown and ultimately erosion. This erosive phenomenon ceased once the electrical stimulation was removed. The end result of this hydrogel erosion is the liberation of the entrapped indomethacin. In vivo animal studies on the SAPD indicated an ‘ON-OFF’ drug release profile. The drug release was consistent and drug quantity of ±0.15mg per release cycle in the Sprague-Dawley rat model. The SAPD was implanted subcutaneously under the left flank and an electrical stimulation was triggered with the use of a 2-in-1 galvano/potentiostat in order to ensure the electrical stimulus was constant. The potential difference used was 1V over a period of 1 minute. The rats were assessed for signs of illness or swelling after the implantation procedure to determine the biocompatibility of the SAPD. The rats were monitored for 10 days and weighed daily. Results have shown that the rats did not experience any considerable swelling and the weights of each rat were steady, thus indicating biocompatibility of the SAPD. Histopatholgical samples indicated mild inflammation around the site of implantation 10 days after implantation. This may have been due to minor surgery at site of implantation. The biocompatibility of the SAPD was generally good and there were no signs of tumour or long term tissue inflammation. Future application of the SAPD may include an external actuation device to be worn as a watch which allows actuation of the SAPD when required by the patient.

Thesis (M.Sc. (Med.) (Pharmaceutical Affairs))--University of the Witwatersrand, Faculty of Health Sciences, 2012