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Zebrafish (Brachydanio rerio) are small, freshwater teleost fishes in the family Cyprinidae, the true minnows. They are native to the tropical latitudes of India, but have become widespread through their use as aquarium fish and as models for several branches of biological research. Their ease of rearing, short generation time, year-around egg laying potential, brief developmental period, and embryo transparency have made them especially desirable as models for developmental biology, genetics, and neurobiology. Because of their popularity, they were also the first small aquarium fish to be used as test organisms for carcinogenesis in the early 1960's. For reasons that have never been stated, their use as a model for carcinogenesis research did not continue. Due to the number of positive characteristics that this species has, the goal of this research effort was to systematically evaluate the potential of zebrafish for use as an environmental monitor, to evaluate the toxicology and carcinogenesis of surface and/or ground waters. The overall project was multidisciplinary in nature, but the focus of this thesis research was on the whole animal, dose-response to a number of well-known carcinogens, administered by multiple exposure routes, and the pathological description of the resulting lesions. Exposure to N-nitrosodiethylamine (DEN) and N-nitrosodimethylamine (DMN) in the diet was ineffective, but static water bath exposure of fry and embryos to these nitrosamines resulted in neoplasms, primarily in the liver. Embryo exposure to DEN resulted in a low response of neoplasms in several other organs as well. Dietary exposure of zebrafish to aflatoxin B₁ resulted in few hepatic neoplasms, revealing a marked resistance to this carcinogen. Dietary exposure to methylazoxymethanol acetate (MAM-Ac) produced mostly liver tumors, as did both fry and embryo water bath exposures. Each water bath exposure also produced neoplasms at other tissue and organ sites, but the embryo stage produced the greatest variety. These results demonstrate a relative resistance to neoplastic development compared to the well-known rainbow trout model. But in one comparative trial, zebrafish were similar to Japanese medaka in their response to dietary MAM-Ac. The major limitation of this species, that will prevent its use as a model for environmental monitoring, however, is its narrow range of temperature tolerance. Temperatures below 15°C produce marked sluggishness, and below 10-12°C cause anesthesia and death. Therefore, this research indicates that this species is not as versatile as some other small fish species for laboratory and especially field monitoring of environmental carcinogenic hazards. / Graduation date: 1997

Purpose: To develop an approach to formulating an injectable solution containing both hydrophilic and lipophilic drugs for subcutaneous administration. Based on the literature survey, isotropic medium chain mono-and diglyceride (MCMDG) systems were chosen for study. For this purpose, analytical methods were developed and validated. In vitro assessments of the MCMDG systems, and in vitro release and in vivo studies were conducted. Methods: The phase diagrams of the isotropic MCMDG systems were constructed with systems comprising two and three components. The isotropic region was examined by visual inspection and confirmed using polarized light microscopy. Viscosities of formulations were measured. The validated HPLC assay methods were developed for determination of levamisole and abamectin in liquid formulations and in sheep plasma. The HPLC assay was capable of evaluating stability of abamectin and levamisole in liquid formulations. Solubilities of levamisole hydrochloride or levamisole phosphate and abamectin were determined in the isotropic MCMDG formulations using a HPLC assay method. Stabilities of levamisole phosphate and abamectin were conducted in the isotropic MCMDG formulations at 60�C for 10 days. In vitro release studies for levamisole phosphate were carried out for selected formulations using modified Franz diffusion cells. Based on stability and in vitro release studies, one formulation (MCMDG/propylene glycol (PG):glycerol formal (GF), 20/20:60 % w/w) was selected for a preliminary in vivo study. The selected MCMDG/PG:GF (20/20:60) formulation containing both levamisole phosphate and abamectin was injected subcutaneously into sheep, and the injection site was examined after subcutaneous injection. Pharmacokinetic profiles were determined. A correlation between in vitro fraction released (FR) and in vivo fraction absorbed (FA) for levamisole phosphate from the MCMDG/PG:GF (20/20:60) formulation was assessed. Results: The isotropic systems of the MCMDG systems containing two or three components were characterized through phase diagrams and viscosity. The solubility of the levamisole hydrochloride in the isotropic MCMDG/sesame oil/water formulations was higher in the absence of abamectin than in combination with abamectin. Solubility of levamisole phosphate was higher in the MCMDG system containing GF or PG compared to the MCMDG/SO/water system. The isotropic MCMDG/PG:GF systems allowed preparations of levamisole phosphate/abamectin solution dose forms containing more than the usual dosage of levamisole. Stability of both levamisole phosphate and abamectin in MCMDG/PG:GF formulations was higher compared with MCMDG/PG:GF/water formulations. Levamisole phosphate degraded in the presence or absence of abamectin in the MCMDG/PG:GF (20/20:60) formulation at 60�C for 10 days. Abamectin alone was found to be stable in the formulation at 60�C for 10 days. In vitro release of levamisole phosphate from water and the MCMDG formulations tested displayed first-order kinetics. Water from the receptor compartment was observed to pass through the membrane into the donor compartment. Therefore, an advancing layer of turbidity occurred in the donor phase. A highly significant decrease in release rate of levamisole phosphate was obtained in MCMDG/GP:GF (20/20:60) formulation compared to water and the other formulations. Pharmacokinetic studies of subcutaneous injection of MCMDG/PG:GF 20/20:60) formulation showed the tmax values of 2.2 h and 4.2 days for levamisole phosphate and abamectin, respectively. The Cmax was 0.94 [mu]g/ml for levamisole phosphate and 6.24 ng/ml for abamectin while the formulation displayed the AUC value was 5.2 [mu]g�h�ml⁻1 for levamisole phosphate and 84.7 ng�day�ml⁻1 for abamectin. No inflammatory reaction was observed at the injection site. Linear regression analysis showed that a significant relationship between the FR (in vitro) and FA for the subcutaneously injected formulation. Conclusion: The study carried out in this thesis introduces a new approach to formulating an injectable solution of the isotropic MCMDG/PG:GF systems containing both levamisole (hydrophilic drug) and abamectin (lipophilic drug) for subcutaneous administration, and presents the development of the HPLC assay methods for determination of levamisole and abamectin in liquid MCMDG formulations and plasma, in order to investigate in vitro and in vivo release from the isotropic MCMDG/PG:GF formulations. The MCMDG/PG:GF formulations may represent an alternative to the more traditional formulations for both lipophilic and hydrophilic drugs.

Bibliography: leaves 193-206. / xiii, 206 leaves : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis investigates the effect of femoral stem surface roughness and a collar on the fixation of cemented hip hemi-arthroplasty femoral stems in an in vivo sheep model up to nine months following implantation. Plain radiography, micromotion between prosthesis and bone during mechanical testing and histology are used. / Thesis (Ph.D.)--University of Adelaide, Dept. of Orthopaedics and Trauma, 1997?