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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.

The synthesis and characterization of complexes analogous to the novel anti-arthritis gold drug auranofin is presented. The general composition of these compounds is L-Au-X where L=triethyl-phosphine and X=tetraacetylthioglucose or chloride in the case of auranofin or its synthetic precursor. Incorporation of ligands (L) such as isocyanides and aromatic nitrogen donors fail to impart the same stability to gold(I) that phosphines or thiols are capable of. Complexes of aromatic nitrogen ligands are prone to decomposition and those of isocyanides, although thermodynamically stable, are labile and subject to relatively rapid isocyanide substitution as well as the expected substitution of the halide group. Complexes have been investigated with regard to their in vitro and in vivo DNA-binding capabilities in light of the reported anticancer properties of auranofin itself. Isocyanide and phosphine gold(I) complexes as well as a series of gold(lll) complexes have shown their ability to bind to DNA in vitro but lose their viability in vivo. This is likely a result of reduction of the gold by thiol groups present in a living system and is associated with the observed cytotoxicity at increasing concentrations. The tris-2-pyridylphosphine (TPP) ligand has also been utilized as a choice for L which has led to the synthesis of the auranofin analogue, (tris-2-pyridylphosphine)(tetraacetylthioglucose)gold(l). Metal ions such as Zn(ll), Co(lll), Cu(ll), Fe(II), Fe(III) and Cr(lll) have been incorporated at the pyridyl nitrogen sites and this series of complexes has been studied crystallographically. N-bound and mixed N-and P-bound complexes have been studied by other techniques as well, depending on the nature of the metal ion involved. Copper(ll) complexes have been investigated by E.S.R. and UV/Visible spectroscopies, Moessbauer data is presented for iron(ll) and iron(lll) complexes and infrared data has been collected and summarized for all complexes. In general, the TPP ligand is an accomodating chelate; N-bound complexes are octahedral and little ligand strain is observed upon coordination. The nitrogen and phosphorus sites are independent in that there appear to be no electronic effects exerted by one site on the other. An important effect of coordinating metal ions to the nitrogen sites is to alter the solubility of the hydrophobic ClAuTPP complex to one with hydrophilic properties. / Thesis / Doctor of Philosophy (PhD)

The development of essential medicines is being slowed by a lack of efficiency in drug development as ninety per cent of drugs fail at some stage during clinical evaluation. This attrition in drug development is seen not because of a reduction in pharmaceutical research expenditure nor is it caused by a declining understanding of biology, if anything, these are both increasing. Instead, drugs are failing because we are unable to effectively predict how they will work before they are given to patients. This is due to limitations of the current methods used to evaluate a drug's toxicity and efficacy prior to its development. Quite simply, these methods do not account for the full complexity of biology in humans. Systems pharmacology models are a likely candidate for increasing the efficiency of drug discovery as they seek to comprehensively model the fundamental biology of disease mechanisms in a quantit- ative manner. They are computational models, designed and hailed as a strategy for making well-informed and cost effective decisions on drug viability and target druggability and therefore attempt to reduce this time-consuming and costly attrition. Using text mining and text classification I present a growing landscape of systems pharmacology models in literature growing from humble roots because of step-wise increases in our understanding of biology. Furthermore, I develop a case for the capability of systems pharmacology models in making predictions by constructing a model of interleukin-6 signalling for rheumatoid arthritis. This model shows that druggable target selection is not necessarily an intuitive task as it results in an emergent but unanswered hypothesis for safety concerns in a monoclonal antibody. Finally, I show that predictive classification models can also be used to explore gene expression data in a novel work flow by attempting to predict patient response classes to an influenza vaccine.

Ko, Wai Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 243-257). / Abstracts in English and Chinese. / Publications Based On The Work In This Thesis --- p.i / Abstract --- p.ii / Acknowledgements --- p.ix / Abbreviations --- p.x / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Prevalence of arthritis --- p.1 / Chapter 1.2 --- Pathogenesis of arthritis --- p.4 / Chapter 1.2.1 --- Histological changes --- p.6 / Chapter 1.2.1.1 --- Synovium changes --- p.6 / Chapter 1.2.1.2 --- Articular cartilage degradation --- p.8 / Chapter 1.2.1.3 --- Bone erosions --- p.10 / Chapter 1.3 --- Western medicines for arthritis --- p.14 / Chapter 1.3.1 --- Nonsteroidal anti-inflammatory drugs (NSAIDs) --- p.15 / Chapter 1.3.2 --- Glucocorticoids (GCs) --- p.18 / Chapter 1.3.3 --- Disease modifying antirheumatic drugs (DMARDs) --- p.20 / Chapter 1.3.4 --- Biological therapies --- p.22 / Chapter 1.4 --- Traditional Chinese medicines for arthritis --- p.24 / Chapter 1.4.1 --- Ganoderma lucidum (靈芝））) --- p.26 / Chapter 1.4.1.1 --- Major chemical constituents --- p.27 / Chapter 1.4.1.2 --- Functions --- p.27 / Chapter 1.4.2 --- Cortex Phellodendri (黃柏） --- p.28 / Chapter 1.4.2.1 --- Major chemical constituents --- p.29 / Chapter 1.4.2.2 --- Traditional description --- p.29 / Chapter 1.4.2.3 --- Functions --- p.30 / Chapter 1.4.3 --- Atractylodisa Rhizoma (蒼术) --- p.31 / Chapter 1.4.3.1 --- Major chemical constituents --- p.31 / Chapter 1.4.3.2 --- Traditional description --- p.32 / Chapter 1.4.3.3 --- Functions --- p.32 / Chapter 1.4.4 --- Radix Achyranthis Bidentatae (牛膝) --- p.33 / Chapter 1.4.4.1 --- Major chemical constituents --- p.34 / Chapter 1.4.4.2 --- Traditional description --- p.34 / Chapter 1.4.4.3 --- Functions --- p.34 / Chapter 1.5 --- Animal models of arthritis --- p.36 / Chapter 1.5.1 --- Adjuvant-induced arthritis --- p.37 / Chapter 1.6 --- Aims of study --- p.42 / Chapter Chapter 2 --- Materials and Drugs --- p.44 / Chapter Chapter 3 --- Methodology --- p.49 / Chapter 3.1 --- Induction of anaesthesia --- p.49 / Chapter 3.2 --- Induction of monoarthritis --- p.49 / Chapter 3.3 --- Measurements of knee extension angles --- p.50 / Chapter 3.4 --- Measurements of knee joint sizes --- p.51 / Chapter 3.5 --- Assessment of changes in articular blood flow --- p.52 / Chapter 3.6 --- Assessment of morphological changes --- p.53 / Chapter 3.6.1 --- Fixation --- p.53 / Chapter 3.6.2 --- Decalcification --- p.53 / Chapter 3.6.3 --- Processing --- p.54 / Chapter 3.6.4 --- Embedding --- p.54 / Chapter 3.6.5 --- Sectioning --- p.55 / Chapter 3.6.6 --- Staining --- p.55 / Chapter 3.6.7 --- Scoring --- p.56 / Chapter 3.7 --- Statistical analysis --- p.57 / Chapter Chapter 4 --- Adjuvant-induced Monoarthritic Rats / Chapter 4.1 --- Adjuvant-induced monoarthritic rats (1 week) --- p.58 / Chapter 4.1.1 --- Method --- p.58 / Chapter 4.1.2 --- Results --- p.59 / Chapter 4.1.2.1 --- Body weight --- p.59 / Chapter 4.1.2.2 --- Knee joint sizes --- p.59 / Chapter 4.1.2.3 --- Knee extension angles --- p.59 / Chapter 4.1.2.4 --- Knee joint blood flow --- p.60 / Chapter 4.1.2.5 --- Histological evaluation --- p.60 / Chapter 4.1.2.5.1 --- Cell infiltration --- p.60 / Chapter 4.1.2.5.2 --- Synovial tissue proliferation --- p.61 / Chapter 4.1.2.5.3 --- Cartilage degradation --- p.61 / Chapter 4.2 --- Adjuvant-induced monoarthritic rats (2 weeks) --- p.68 / Chapter 4.2.1 --- Method --- p.68 / Chapter 4.2.2 --- Results --- p.69 / Chapter 4.2.2.1 --- Body weight --- p.69 / Chapter 4.2.2.2 --- Knee joint sizes --- p.69 / Chapter 4.2.2.3 --- Knee extension angles --- p.69 / Chapter 4.2.2.4 --- Knee joint blood flow --- p.70 / Chapter 4.2.2.5 --- Histological evaluation --- p.70 / Chapter 4.2.2.5.1 --- Cell infiltration --- p.70 / Chapter 4.2.2.5.2 --- Synovial tissue proliferation --- p.71 / Chapter 4.2.2.5.3 --- Cartilage degradation --- p.71 / Chapter 4.3 --- Discussions --- p.78 / Chapter Chapter 5 --- Effects of intra-articular injection of LS in adjuvant-induced monoarthritic rats --- p.82 / Chapter 5.1 --- Method --- p.82 / Chapter 5.2 --- Results --- p.83 / Chapter 5.2.1 --- Body weight --- p.83 / Chapter 5.2.2 --- Knee joint sizes --- p.83 / Chapter 5.2.3 --- Knee extension angles --- p.85 / Chapter 5.2.4 --- Knee joint blood flow --- p.87 / Chapter 5.3 --- Discussions --- p.98 / Chapter Chapter 6 --- Effects of oral administration of LS in adjuvant-induced monoarthritic rats --- p.102 / Chapter 6.1 --- Oral administration of LS for 6 days after induction of arthritis --- p.102 / Chapter 6.1.1 --- Method --- p.102 / Chapter 6.1.2 --- Results --- p.103 / Chapter 6.1.2.1 --- Body weight --- p.103 / Chapter 6.1.2.2 --- Knee joint sizes --- p.103 / Chapter 6.1.2.3 --- Knee extension angles --- p.105 / Chapter 6.1.2.4 --- Knee joint blood flow --- p.106 / Chapter 6.1.2.5 --- Histological evaluation --- p.107 / Chapter 6.1.2.5.1 --- Cell infiltration --- p.107 / Chapter 6.1.2.5.2 --- Synovial tissue proliferation --- p.107 / Chapter 6.1.2.5.3 --- Cartilage degradation --- p.108 / Chapter 6.2 --- Oral administration of LS for 7 days before and 7 days after induction of arthritis --- p.131 / Chapter 6.2.1 --- Method --- p.131 / Chapter 6.2.2 --- Results --- p.132 / Chapter 6.2.2.1 --- Body weight --- p.132 / Chapter 6.2.2.2 --- Knee joint sizes --- p.132 / Chapter 6.2.2.3 --- Knee extension angles --- p.134 / Chapter 6.2.2.4 --- Knee joint blood flow --- p.137 / Chapter 6.2.2.5 --- Histological evaluation --- p.137 / Chapter 6.2.2.5.1 --- Cell infiltration --- p.137 / Chapter 6.2.2.5.2 --- Synovial tissue proliferation --- p.138 / Chapter 6.2.2.5.3 --- Cartilage degradation --- p.138 / Chapter 6.3 --- Oral administration of LS for 13 days after induction of arthritis --- p.165 / Chapter 6.3.1 --- Method --- p.165 / Chapter 6.3.2 --- Results --- p.166 / Chapter 6.3.2.1 --- Body weight --- p.166 / Chapter 6.3.2.2 --- Knee joint sizes --- p.166 / Chapter 6.3.2.3 --- Knee extension angles --- p.168 / Chapter 6.3.2.4 --- Knee joint blood flow --- p.169 / Chapter 6.3.2.5 --- Histological evaluation --- p.170 / Chapter 6.3.2.5.1 --- Cell infiltration --- p.170 / Chapter 6.3.2.5.2 --- Synovial tissue proliferation --- p.170 / Chapter 6.3.2.5.3 --- Cartilage degradation --- p.171 / Chapter 6.4 --- Discussions --- p.194 / Chapter Chapter 7 --- Effects of intra-peritoneal administration of LS in adjuvant-induced monoarthritic rats --- p.203 / Chapter 7.1 --- Method --- p.203 / Chapter 7.2 --- Results --- p.204 / Chapter 7.2.1 --- Body weight --- p.204 / Chapter 7.2.2 --- Knee joint sizes --- p.205 / Chapter 7.2.3 --- Knee extension angles --- p.207 / Chapter 7.2.4 --- Knee joint blood flow --- p.209 / Chapter 7.2.5 --- Histological evaulation --- p.209 / Chapter 7.2.5.1 --- Cell infiltration --- p.209 / Chapter 7.2.5.2 --- Synovial tissue proliferation --- p.210 / Chapter 7.2.5.3 --- Cartilage degradation --- p.210 / Chapter 7.3 --- Discussions --- p.237 / Chapter Chapter 8 --- Conclusions --- p.239 / References --- p.243