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Abstract not available

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No description available.

Doxorubicin is one of the most effective anti-cancer agents; however its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Mitochondrial function and integrity are crucial for cellular processes in general and play an important role during diseased development. These characteristics of the mitochondria make them the prime target for treatments for majority of diseases and in particular of the cardiovascular system. The mitochondria are also considered to play an integral role in the manifestation of the cardiotoxic effects of compounds such as doxorubicin. The current project is designed to investigate the cardiotoxic effects of doxorubicin at tissue, cellular and protein level. In addition, it is investigated whether the inhibition of the mitochondrial permeability transition pore (mPTP) with cyclosporin A (CsA) or the inhibition of mitochondrial fission with the mitochondrial division inhibitor (mdivi-1) protects against the detrimental effects of doxorubicin on cardiac function. We also investigated whether co-treatment of doxorubicin with either CsA or mdivi-1 has any negative interaction with the cytotoxicity of doxorubicin against cancer cells. Langendorff results indicated that doxorubicin caused a time dependent reduction in the haemodynamic function of the heart as well as causing an increase in the infarct size to risk ratio in both naïve conditions and in conditions of ischaemia and reperfusion. Detrimental effects of doxorubicin on cardiac function were abrogated by co-treatment of doxorubicin with CsA or mdivi-1 in naïve conditions and in conditions of ischaemia and reperfusion. Cell viability data of isolated cardiac myocytes revealed that doxorubicin caused a concentration dependant decrease in the viability of neonatal cardiac myocytes as well as causing a reduction in the time taken to depolarisation and hypercontracture under sustained oxidative stress, all of which were prevented when co-treated with either CsA or mdivi-1. Doxorubicin significantly elevated the levels of p-Akt, p-Erk, p-Drp1 and p-p53. Co-treatment with CsA prevented the increase in the levels of p-Akt and p-Erk caused by doxorubicin in both naïve and IR condition whereas mdivi-1 prevented the increase in the levels of p-Erk, p-Drp1 and p-p53 and caused further increase in the levels of p-Akt. Using sinusoidal muscle length change during contraction and relaxation, it is demonstrated that doxorubicin caused a decrease in the power output, peak force and force during shorting. Detrimental effects of doxorubicin on work-loop contraction were abrogated when doxorubicin was co-administered with CsA. To conclude, results demonstrated that doxorubicin caused cardiotoxicity at tissue, cellular and protein level in both naïve conditions and in conditions of ischaemia and reperfusion injury. In addition, it is shown that the inhibition of mitochondrial permeability transition pore with CsA or the inhibition of the mitochondrial fission with mdivi-1 protect against doxorubicin-induced toxicity without affecting its anti-cancer properties.

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Corrigenda inserted opposite title page. / Copies of author's previously published articles inserted inside back cover. / Bibliography: leaves 245-291. / xvii, 291 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / An improved HPLC method was developed to measure the concentration of the three compounds in plasma and urine. The stability of the compounds during storage in plasma was also established. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1995?

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Corrigenda inserted opposite title page. / Copies of author's previously published articles inserted inside back cover. / Bibliography: leaves 245-291. / xvii, 291 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / An improved HPLC method was developed to measure the concentration of the three compounds in plasma and urine. The stability of the compounds during storage in plasma was also established. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1995?

Philosophiae Doctor - PhD / Conscious sedation or moderate sedation and analgesia is an effective and popular alternative option for procedures outside the operating theater. If conscious sedation is a viable alternative to general anaesthesia then we as sedation practitioners must use safe sedation techniques in facilities that meet all the requirements for safe practice. Three studies were done to determine the safety and efficacy of conscious sedation outside the operating theatre. In the first study post sedation satisfaction in one hundred children aged 3-9 years was evaluated. It was extremely important to determine whether the combination of midazolam, ketamine and propofol, called an advanced sedation technique (SASA, 2015), can be safely used for paediatric sedation outside the operating theatre. The incidence of side-effects after conscious sedation using multiple drugs were documented. It is clear that intravenous sedation with midazolam, ketamine and propofol is safe and effective to use. There may be side effects but they are not long lasting and usually not life-threatening. In the second study intravenous sedation was administered to 447 adults (aged 18 years and older) using fentanyl (sublimazeR), ketamine (ketalar), midazolam (dormicum) and propofol (Diprivan) (FKMP) called an advanced sedation technique. Post sedation satisfaction, post sedation recovery on arrival home, and the relationship between side effects and different dental procedures were evaluated. The results of the study show that side effects are possible, and can be expected, when we use sedative and analgesic drugs for sedation. However, we report a low incidence of side effects when we compare it with other studies in literature as mentioned. It is known that the use of combinations of drugs may cause unforeseen synergistic pharmacological effects which can be lifethreatening. Our results show that the drugs used can be safely used for advanced sedation techniques. In trying to demonstrate the safety of sedative and analgesic agents used during sedation we looked at the haemodynamic parameters, duration of sedation, pulse rate and systolic blood pressure, in the third study. The sedation records of 335 patients for dental surgery were assessed for the period 2010 – 2011. Our results show the mean Duration of sedation is substantially and statistically significantly greater with combination FKMP than with the other combinations. The mean duration of sedation is not significantly different between ketamine and propofol (KP) and fentanyl, ketamine and propofol (FKP) (Figure 10). The use of polypharmacy regarding the combination of drugs, specifically FKMP, will cause a longer duration of sedation. This has implications for safety, as well as the side effect profile during and after sedation. When we use combinations of drugs patients were more comfortable which shows that we do not yet have a single drug that has all the characteristics of an ideal drug for sedation. Different combinations of drugs are used by other practitioners with a higher incidence of side effects. It is difficult to explain the higher values of blood pressures when all four drugs were used. It may have been a ketamine effect, although one would not expect this when using propofol with ketamine. In clinical terms the higher blood pressures are no reason for concern as all our patients were classified as ASA I and II. Our research study support the view that ketamine can be used safely outside the operating theatre with exciting possibilities for Third World countries for procedures outside the operating theatre. Sedation can be considered a reasonable alternative to general anaesthesia for certain surgical procedures in the Third World. Sedation will be an attractive option not only as far as costs are involved but also the availability of sedation providers. The important lesson from all the results is that sedation providers must be trained in procedural sedation as defined by all international sedation guidelines. We proved in this research study that sedation can be done safely, however we need to make a contribution to train sedation providers. Sedation will become an attractive alternative to general anaesthesia because of the low side-effect profile and high patient satisfaction. It is interesting that few studies are available that looked at this aspect of sedation. It is clear that a high side-effect profile can contribute to an unsafe sedation technique. Severe nausea and vomiting can cause numerous haemodynamic disturbances and dehydration. Our research study support the findings of the study by Lapere et al., (2015) that there is a high rate of patient satisfaction, and a low side-effect profile during and after sedation. This is an extremely important research study and the results are crucial as far as an option for healthcare in developing countries. Sub-Saharan Africa is a densely populated and resource poor subcontinent that provides unique challenges in patient care. These challenges include a lack of facilities and staff for the performance of operative as well as non-operative procedures. In conclusion, we feel that we are part of Sub-Saharan Africa with all the problems mentioned as far as provision of healthcare is concerned. This research study can make a crucial contribution to safe and cost-effective management of healthcare in Africa for procedures outside the operating theatre.