3. Electronic Theses and Dissertations (ETDs) - All submissions

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    Development of a novel rate-modulated fixed dose analgesic combination for the treatment of mild to moderate pain
    (2010-09-17) Hobbs, Kim Melissa
    Pain is the net effect of multidimensional mechanisms that engage most parts of the central nervous system (CNS) and the treatment of pain is one of the key challenges in clinical medicine (Le Bars et al., 2001; Miranda et al., 2008). Polypharmacy is seen as a barrier to analgesic treatment compliance, signifying the necessity for the development of fixed dose combinations (FDCs), which allow the number of tablets administered to be reduced, with no associated loss in efficacy or increase in the prevalence of side effects (Torres Morera, 2004). FDCs of analgesic drugs with differing mechanisms of nociceptive modulation offer benefits including synergistic analgesic effects, where the individual agents act in a greater than additive manner, and a reduced occurrence of side-effects (Raffa, 2001; Camu, 2002). This study aimed at producing a novel, rate-modulated, fixed-dose analgesic formulation for the treatment of mild to moderate pain. The fixed-dose combination (FDC) rationale of paracetamol (PC), tramadol hydrochloride (TM) and diclofenac potassium (DC) takes advantage of previously reported analgesic synergy of PC and TM as well as extending the analgesic paradigm with the addition of the anti-inflammatory component, DC. The study involved the development of a triple-layered tablet delivery system with the desired release characteristics of approximately 60% of the PC and TM being made available within 2 hours to provide an initial pain relief effect and then sustained zero-order release of DC over a period of 24 hours to combat the on-going effects of any underlying inflammatory conditions. The triple-layered tablet delivery system would thus provide both rapid onset of pain relief as well as potentially address an underlying inflammatory cause. The design of a novel triple-layered tablet allowed for the desired release characteristics to be attained. During initial development work on the polymeric matrix it was discovered that only when combined with the optimized ratio of the release retarding polymer polyethylene oxide (PEO) in combination with electrolytic-crosslinking activity, provided by the biopolymer sodium alginate and zinc gluconate, could the 24 hour zero-order release of DC be attained. It was also necessary for this polymeric matrix to be bordered on both sides by the cellulosic polymers containing PC and TM. Thus the application of multi-layered tableting technology in the form of a triple-layered tablet were capable of attaining the rate-modulated release objectives set out in the study. The induced barriers provided by the three layers also served to physically separate TM and DC, reducing the likelihood of the bioavailability-diminishing interaction noted in United States Patent 6,558,701 and detected in the DSC analysis performed as part of this study. The designed system provided significant flexibility in modulation of release kinetics for drugs of varying solubility. The suitability of the designed triple-layered tablet delivery system was confirmed by a Design of Experiments (DoE) statistical evaluation, which revealed that Formulation F4 related closest to the desired more immediate release for PC and TM and the zero-order kinetics for DC. The results were confirmed by comparing Formulation F4 to typical release kinetic mechanisms described by Noyes-Whitney, Higuchi, Power Law, Pappas-Sahlin and Hopfenberg. Using f1 and f2 fit factors Formulation F4 compared favourably to each of the criteria defined for these kinetic models. The Ultra Performance Liquid Chromatographic (UPLC) assay method developed displayed superior resolution of the active pharmaceutical ingredient (API) combinations and the linearity plots produced indicated that the method was sufficiently sensitive to detect the concentrations of each API over the concentration ranges studied. The method was successfully validated and hence appropriate to simultaneously detect the three APIs as well as 4-aminophenol, the degradation product related to PC. Textural profile analysis in the form of swelling as well as matrix hardness analysis revealed that an increase in the penetration distance was associated with an increase in hydration time of the tablet and also an increase in gel layer thickness. The swelling complexities observed in the delivery system in terms of both the PEO, crosslinking sodium alginate and both cellulose polymers as well as the actuality of the three layers of the tablet swelling simultaneously suggests further intricacies involved in the release kinetics of the three drugs from this tablet configuration. Modified release dosage forms, such as the one developed in this study, have gained widespread importance in recent years and offer many advantages including flexible release kinetics and improved therapy and patient compliance.
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    Physical abilities of community-dwelling adults more than six months post stroke: a cross sectional survey
    (2010-06-25T09:28:52Z) Dearle, Luschka Anne
    Background and purpose of the study The length of stay for patients with stroke in some South African government hospitals has been shown to be inadequate and there is little information on the physical impairments and functional abilities of this population once they return to the community. An assessment was done of the strength, range of movement and the presence of pain experienced by patients with stroke in the Daveyton community and the relationship between these impairments and the functional abilities of these patients was established. Research methods and procedures employed This was a quantitative study using a descriptive cross sectional study design. Thirty-four conveniently sampled patients with stroke were assessed in their Daveyton homes. The functional measures used were the Modified rivermead mobility index (MRMI) and Barthel index (BI). The strength was assessed using a hand-held dynamometer, range of movement (RoM) with a standard universal goniometer and pain with the Eleven faces pain scale. The significance of the study was set at 0.05 and the relationships between impairments and functional abilities were expressed using the Spearman’s rank correlation coefficient. Results Significant differences were found between the strength, as well as the RoM of the affected and unaffected sides (p < 0.05). The muscles most affected by were: Biceps, Gastrocnemius and Tibialis Anterior. The smallest strength difference was found in Gluteus maximus. The ranges of movement most affected were: shoulder flexion and elbow extension. The smallest difference was found in knee extension. Eighty-five percent of the sample attained scores indicating that they were independently mobile (measured by the MRMI), and 82% were independent in activities of daily living (measured by the BI). There were good correlations between the patients’ strength impairments and their functional abilities (r = 0.54 to 0.79) and mobility (r = 0.51 to 0.76). Functional abilities and mobility had moderate to good relationships with active range of movement of shoulder flexion, lateral shoulder rotation and dorsiflexion. The percentage of patients experiencing pain was 73%, but pain displayed no relationship with functional ability (r = 0.14) and mobility (r = 0.15). Conclusion Most people living with stroke in the Daveyton community are functionally independent despite the high prevalence of pain. Stroke results in significant strength and active range of movement deficits on the affected side. Most strength impairments correlated well with the functional ability and mobility of this sample, but active range of movement impairments that influenced functional measures were mainly shoulder and ankle movements.
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    The pathophysiology of UVA-light induced hyperalgesia
    (2009-09-08T09:27:47Z) Themistocleus, Andreas Constantinos
    In this thesis I describe the development of an animal model of sustained hyperalgesia induced by exposure to ultraviolet (UV) A light to the rat’s tail, and the role of the Cfibre barrage and peripheral afferent fibre sensitization in this model of hyperalgesia. Exposure of rats’ tails to UVA-light caused hyperalgesia to a noxious thermal challenge, immersion of the rats’ tails into 49°C water, and a noxious mechanical challenge, application of a static force of 3.9N by a bar algometer onto the rats’ tails. The hyperalgesia to the thermal challenge lasted eight days and hyperalgesia to the mechanical challenge continued for up to 16 days. Despite the sustained hyperalgesia, rats exposed to UVA-light showed no overt signs of morbidity as they gained weight normally and were mobile throughout the study. Histological examination of rat tail tissue showed mild, chronic inflammation in rats exposed to UVA-light and in rats that had their tails covered with a protective layer of aluminium foil during UVA-light exposure. This inflammation was therefore not responsible for the behavioural hyperalgesia. To investigate the role of C-fibre barrage in the development of hyperalgesia after UVA-light exposure, I pre-emptively blocked C-fibre activation during UVA-light exposure with the local anaesthetic bupivacaine. Injection of bupivacaine (1ml of 0.5%), into the base of the tail prevented the development of thermal hyperalgesia to tail immersion in 49°C water. However, it did not prevent the development of hyperalgesia to a noxious punctate challenge. Thus the sustained mechanical hyperalgesia did not depend on the activation of the C-fibre barrage, but thermal hyperalgesia did depend on the activation of a C-fibre barrage during the conditioning event of UVA-light exposure. Lastly, in rats anaesthetised with enflurane, I examined the responses of coccygeal primary afferent fibres to noxious thermal and mechanical stimulation after UVA-light exposure of their receptive fields on the tail. I investigated only pure nociceptive afferents and ignored those afferents that responded to challenges in the noxious and non-noxious ranges. The peak firing rates and areas under the curve of post-challenge histograms, a measure of neuronal firing over time, of Ad- and C-fibres were increased when noxious blunt and punctate challenges were applied to the rats’ tails after UVA-light exposure, showing that Ad- and C-fibres that encode for noxious mechanical challenges were sensitized. The peak firing rate of C-fibres that were responsive to noxious thermal challenges were not increased after UVA-light exposure. Therefore, thermal hyperalgesia was probably mediated by sensitization of central nervous system neurones. In summary, I developed a model of sustained mechanical and thermal hyperalgesia caused by UVA-light exposure of the rat tail. The thermal hyperalgesia was initiated by the C-fibre barrage, while mechanical hyperalgesia did not depend on the C-fibre barrage and peripheral afferent sensitization of Ad- and C-fibres could account for the mechanical hyperalgesia.
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    The effect of Pilates on patients’ chronic low back pain. A pilot study.
    (2006-11-10T11:50:38Z) MacIntyre, Leanne
    The Pilates exercise method applies many of the principles of lumbar stabilisation that have been found to be effective in the treatment of chronic low back pain. Pilates has recently found its way into the physiotherapy setting, where it is being integrated into the rehabilitation of patients with low back pain. This study consisted of a randomised control trial using an intervention group that underwent a twelve-week Pilates programme, and control group that continued with standardised physiotherapy treatment as necessary. Baseline, three-week, and twelve-week scores for a Visual Analogue Scale for pain and the Roland Morris Disability Questionnaire were recorded and compared. The Pilates group showed significantly greater improvements in pain and functional disability mean scores when compared to the control group (p=0.059 and p=0.026 respectively). It therefore appears that Pilates can be recommended as an effective treatment modality for the reduction of pain and the improvement of functional disability for chronic low back pain sufferers.
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