Includes bibliography. / 88 leaves, [18] leaves of plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 1990

Thesis (PhD)--University of South Australia, 1995

The rise of large scale agriculture in the 20th century created the need for effective strategies to control insect pests. Treatment with chemical insecticides has been a weapon of choice, but the inevitable evolution of resistance has followed in many insect species. Resistance represents a major challenge, not only for agricultural production, but also for environmental preservation and human health. Two major options for resistance have been identified, and these are target-site based and metabolic-based resistance. Much insecticide resistance research focuses on identifying these mechanisms through genetic and molecular analysis. The insecticide lufenuron is the focus of this study. It belongs to a novel insecticidal group called the insect growth regulators, which were introduced in 1970s as highly selective insecticides with low vertebrate toxicity. Resistance to lufenuron in the non-pest species Drosophila melanogaster has been observed in field populations, despite the lack of field usage of lufenuron (Wilson & Cain, 1997; O’Keefe, 1997). This study has taken advantage of this phenomenon to investigate resistance mechanisms in natural populations. At least two detoxification mechanisms were identified. (For complete abstract open document)

Master of Philosophy / Clozapine is a drug of choice for treatment of refractory schizophrenia, which is primarily metabolized by Cytochrome P450 1A2 (CYP1A2). Norclozapine is its main metabolite. There are reports of wide ranging gastrointestinal side effects associated with clozapine therapy, that result in concomitant administration of proton pump inhibitors to treat acid-related disorders. Omeprazole is an established CYP1A2 inducer, while an in vitro study has shown that rabeprazole is much less potent in this regard. There is no available information about the impact of rabeprazole on CYP1A2 activity in patients. Firstly, this information is essential when prescriptions are changed from omeprazole to rabeprazole to reduce medication costs. Therefore, the aim of this study was to compare the effects of rabeprazole and omeprazole on CYP1A2-mediated clearance (CL/F) of clozapine. Secondly, the effective dosage of clozapine varies widely among patients, making it necessary to individualize drug therapy with clozapine. The reason for dosage variation could be due to the influence of patient-related variables on clozapine plasma concentrations. Therefore, another aim of this study was to investigate the relationship between patient variables, such as age, gender, cigarette smoke, weight and body mass index and clozapine clearance (CL/F). A cross-over study design was used for this study. Twenty patients from Macquarie hospital who were receiving clozapine and rabeprazole (with no other interacting medications) were recruited in this study. Blood samples were taken at 30 min, 1 hr, 2 hr and 12 hr after a dose of clozapine. Rabeprazole was then replaced with omeprazole. After at least 1 month blood samples were again collected at the above corresponding intervals after clozapine. The plasma concentrations of clozapine and norclozapine were determined by high performance liquid chromatography. Abbottbase Pharmacokinetic Systems Software, which utilizes Bayesian forecasting, was used to estimate pharmacokinetic parameters of clozapine. The ratio of plasma norclozapine/clozapine concentrations at trough level was used to reflect CYP1A2 activity. No difference was observed in clozapine clearance (CL/F) and CYP1A2 activity during concurrent therapy with either rabeprazole or omeprazole. According to some studies CYP1A2 induction by omeprazole is dose dependent. Furthermore, since rabeprazole is a weak CYP1A2 inducer in vitro, we conclude that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40 mg/day). Hence, replacement of omeprazole with rabeprazole at conventional therapeutic dosages (20 or 40 mg daily) offers no advantages in the management of patients with schizophrenia on clozapine and no dose adjustment is required. Consistent with previous studies, clozapine concentrations were found to be significantly lower in cigarette smokers due to CYP1A2 induction. No relationship was found between age, gender, or weight and clozapine clearance (CL/F). However, body mass index showed a significant negative correlation with clozapine clearance (CL/F). Since weight gain and lipid accumulation are common side effects of clozapine they may be associated with a reduction of CYP1A2 activity and clozapine clearance (CL/F). Moreover, high lipoprotein levels may decrease the unbound fraction of clozapine and decrease the availability of clozapine for oxidation by cytochrome P450 enzymes. Therefore, it is concluded that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40mg/day). Hence, replacement of omeprazole with rabeprazole does not require the dose of clozapine to be adjusted. Moreover, the negative correlation between clozapine clearance (CL/F) and BMI is informative. Further studies are now required to clarify the relationship between BMI, lipoprotein levels and clozapine clearance in patients with schizophrenia.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 6 uppsatser.

Thesis (Ph.D.)--University of Western Australia, 2004.

Thesis (M. Phil.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Washington, 1997. / Vita. Includes bibliographical references (leaves [81]-115).

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [162]-177).