published_or_final_version / Biochemistry / Master / Master of Science

Typescript (photocopy). / Digitized by Kansas Correctional Industries

Reported here is an investigation to determine if azinphos-methyl (AZM), an organophosphate insecticide, adducts to hemoglobin, and if so, whether the hemoglobin adduct could be used as a quantitative marker of occupational AZM exposure. We hypothesized that AZM, or a metabolite of AZM, binds to hemoglobin in erythrocytes forming an adducted protein. We administered radiolabled AZM to rats and found a stable, dose-dependent association of radioactivity with hemoglobin. The decline in hemoglobin-associated radioactivity followed the expected kinetics of erythrocyte turnover in rats. We examined hemoglobin isolated from these rats by high-pressure liquid chromatography, liquid scintillation counting, and electrospray ionization mass spectrometry. These analyses provided evidence of AZM or an AZM metabolite binding to one of the beta proteins of hemoglobin. In vitro incubation of AZM with hemoglobin in a liver microsome system indicated an AZM adduct to heme. Further research is necessary to fully characterize the adduct and determine whether this biomarker will be useful for monitoring human exposure to AZM. / Graduation date: 2000

The work in this dissertation aims to describe a simple new test for odor-recognition memory in rats that can be readily performed and results in an easily observable and lasting form of memory. This test has allowed for the demonstration of ethanol-induced retrograde memory impairments in rats when ethanol is administered during both the consolidation and reconsolidation phases of memory encoding. The observation that a high-dose of ethanol can cause retrograde memory impairments when administered immediately or within hours after learning has taken place is an original finding that may have implications for understanding human blackouts. Furthermore, the finding that ethanol can disrupt the reconsolidation of a previously consolidated memory has not been previously established. It is also demonstrated that caffeine can prevent ethanol’s memory impairing effects, a result that contributes a new piece of evidence for caffeine’s effects on the learning and memory process. This effect has been further investigated mechanistically and attributed to caffeine’s dual role as a phosphodiesterase type 5 inhibitor and adenosine A2A antagonist. Neither of these mechanisms alone appear to be sufficient enough to prevent the retrograde memory impairments seen with ethanol. It is hoped that this test and our findings will prove useful for future investigations into the effects of ethanol on learning and memory and the human phenomenon of alcohol-induced blackouts. / text

Part I. In order to determine the effect of dose size on the bioavailability of phenytoin (Dilantinᴿ), a single intravenous dose of 15 mg/kg, single oral doses of 400, 800, 1600 mg, and 1600 mg in divided doses (i.e. 400 mg every three hours) were administered to six healthy male subjects. Values of V(max) and K(m) obtained from the intravenous dose were used to determine the extent of absorption from the oral doses. Although no statistically significant difference in extent of phenytoin absorption was observed, the time to reach maximum phenytoin serum concentrations increased significantly from 8.4 hours for the 400 mg dose and 13.2 hours for the 800 mg dose to 31.5 hours for the 1600 mg dose. Peak serum concentrations of 3.9, 5.7, 10.7, and 15.3 mg/1 were observed after the 400, 800, 1600 and 1600 mg divided doses, respectively. It is suggested that the prolonged, but complete, absorption of large phenytoin doses is due to a slow dissolution and continued absorption from the colon. Owing to the prolonged absorption of phenytoin, it may be necessary to use a larger oral than intravenous loading dose to produce similar maximum phenytoin serum concentrations. Part II. The effects of age and obesity on the pharmacokinetics of thiopental were studied in 7 morbidly obese (aged 25 to 46 years) and 22 lean patients (aged 25 to 83 years), who were primarily undergoing abdominal surgery. In all 29 patients, serum thiopental concentrations were determined by gas-liquid chromatography using a nitrogen-selective detector. Based upon total (bound+free) thiopental concentrations, the average (±S.E.) volumes of distribution (Vᵦ and V(ss)) were significantly larger in the obese (7.94 ± 1.72 1/kg and 4.72 ± 1.03 1/kg, respectively) than in the age-matched lean patients (1.95 ± 0.22 1/kg and 1.40 ± 0.16 1/kg, respectively). Clearance based on total thiopental concentrations normalized to total body weight (TBW) was not significantly different between the obese (0.18 ± 0.03 1/hr/kg) and lean patients (0.21 ± 0.02 1/hr/kg). However, total body clearance not normalized to TBW was significantly larger in the obese (24.98 ± 5.62 1/hr) than in the lean patients (11.86 ± 1.29 1/hr). The half-life of thiopental was significantly larger in the obese (31.87 ± 4.53 hours) than in the lean patients (6.61 ± 0.52 hours) and was primarily a function of the larger apparent volume of distribution for thiopental. The unbound fraction of thiopental in serum (range, 17.8% to 27.6%) did not depend on the degree of obesity, but was found to be greater with advancing age. The apparent volumes of distribution, Vᵦ and V(ss), were also related to age. No significant relationship was found between total body clearance with increasing age. Thus, the half-life of thiopental was positively correlated with age, and as in the obese study, was found to be primarily influenced by the apparent volume of distribution.

No description available.

No description available.

There has been a great deal of research investigating drug combinations which can increase analgesia. A number of studies have been conducted with one particular combination--opioids combined with the amphetamine drugs. Despite the existing literature, this combination is rarely used in clinical practice. One purpose of this thesis is to review the literature pertaining to the opioid-amphetamine combination. Another purpose of this thesis is to investigate whether dextroamphetamine sulfate ($ circler$Dexedrine) can potentiate morphine sulfate analgesia in rats in the formalin test (Experiment 1). To investigate whether these results can be generalized to another psychostimulant, methylphenidate hydrochloride ($ circler$Ritalin) is used in Experiment 2. Methylphenidate has been chosen instead of another amphetamine drug because it is currently being used in clinical studies without supporting evidence from animal studies. The results of the two experiments indicate that low doses of d-amphetamine and methylphenidate can potentiate the analgesic effects of morphine.

1 v. (various paging) : ill. ; 26 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.1976) from the Dept. of Human Physiology and Pharmacology, University of Adelaide

No description available.