Thesis (Ph. D.)--Illinois State University, 1987. / Title from title page screen, viewed August 22, 2005. Dissertation Committee: Robert L. Preston (chair), George W. Kidder, Jim N. Tone, John L. Frehn, Wayne A. Riddle. Includes bibliographical references (leaves 209-216) and abstract. Also available in print.

Thesis (Ph. D.)--Columbia University, 1922. / Vita. Description based on print version record. Bibliography: 1 p. following p. 32.

Thesis (Ph. D.)--Columbia University, 1926. / Vita. Bibliography: [3] p. at end.

Thesis (Ph. D.)--Columbia University, 1941. / Vita. "Literature cited": p. 28.

Formic acid and nitric acid have been found to contribute to aerosol formation and are key components of acidity in the troposphere. Tropospheric measurements of these species are often limited, resulting in major uncertainties when assessing their effects on the climate. Current global chemistry-transport models significantly under-predict formic acid concentrations, particularly in the mid-to-high latitudes of the Northern Hemisphere. Furthermore, large discrepancies exist in the role played by dinitrogen pentoxide on nitric acid production between two recently documented models assessing the global nitric acid budget. In order to accurately constrain the budget of these acids in the mid-to-high latitudes of the Northern Hemisphere, it is crucial that these uncertainties are addressed. In this work, airborne measurements of formic acid, nitric acid and dinitrogen pentoxide are presented from across different regions of the Northern Hemisphere to investigate direct and indirect sources contributing to the formic acid and nitric acid regional budgets. Measurements were collected using a Chemical Ionisation Mass Spectrometer (CIMS) fitted to the Facility for Atmospheric Airborne Measurements (FAAM) BAe-146 aircraft. Formic acid measurements within the European Arctic during March and July 2012 would indicate ocean sources dominate over terrestrial sources irrespective of seasonality. CH2I2 photolysis and oxidation was hypothesised as a marine source of formic acid. Modelled estimates would indicate the CH2I2 reaction route may represent a significant summer marine source of formic acid within the Fenno-Scandinavian Arctic. Additionally, low altitude aircraft measurements taken within the Fenno-Scandinavian Arctic over regions occupied by wetlands in August 2013 were used to calculate a formic acid surface flux. Results would suggest formic acid emission from wetlands may represent up to 37 times greater than its globally inferred estimate. A flux measurement conducted over a comparable region in September 2013 observed a negative flux, indicating a change of this region from a net source to a net sink of formic acid. The inconsistency of this regional wetland source confirms the need for in-depth studies on formic acid emission from wetlands, in order to better understand its contribution to the regional and global formic acid budget. In a separate study, significant daytime elevations of N2O5 and HNO3 concentrations were observed within identified biomass burning plumes off the eastern coast of Canada. In-plume correlations between N2O5 and HNO3 concentrations observed within these environments suggest N2O5 was acting as additional daytime source of gaseous HNO3 when subjected to photolytically-limited conditions. This result has important implications to ozone production and provides evidence for an additional daytime source of nitric acid, which must be included in chemistry models calculating the global nitric acid budget.

Cyanobacteria (blue-green algae) produce a diverse array of toxic or otherwise bioactive metabolites. These allelochemicals may also play a role in defense against potential predators and grazers, particularly aquatic invertebrates and their larvae, including mosquitoes. Compounds derived from cyanobacteria collected from the Florida Everglades and other Florida waterways were investigated as insecticides against the mosquito Aedes aegypti, a vector of dengue and yellow fever. Screening of cyanobacterial biomass revealed several strains that exhibited mosquito larvicidal activity. Guided via bioassay guided fractionation, a non-polar compound from Leptolyngbya sp. 21-9-3 was found to be the most active component. Characterization revealed the prospective compound to be a monounsaturated fatty acid with the molecular formula C16H30O2. This is the first evidence of mosquito larvicidal activity for this particular fatty acid. With larvicidal becoming more prevalent, fatty acids should be explored for future mosquito control strategies.

The potential for conjugated linoleic acid (CLA) incorporation into pressure-sensitive adhesive (PSA) formulations was evaluated. A series of free radical bulk copolymerizations of CLA/styrene (Sty) and CLA/butyl acrylate (BA) were designed to allow the estimation of reactivity ratios. Bulk terpolymerizations of CLA/Sty/BA were also evaluated before moving to emulsion terpolymerizations of CLA/Sty/BA. The polymers were characterized for composition, conversion, molecular weight and glass transition temperature while latexes were characterized for viscosity, particle size, tack, peel strength, and shear strength. All experiments were performed at 80oC and monitored with attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. While bulk experiments were monitored off-line, the emulsion experiments were monitored in-line. Absorbance peaks related to the monomers and polymer were tracked to provide conversion and polymer composition data using a multivariate calibration method. Off-line measurements using gravimetry and 1H-NMR spectroscopy were compared to the ATR-FTIR data and no significant differences were detected between the measurement methods. Pseudo-kinetic models, developed and validated with the copolymer experimental data, were used to estimate reactivity ratios. The copolymer pseudo-kinetic models were extended to a terpolymer pseudo-kinetic model and validated with experimental data. The pseudo-kinetic models incorporated the ability of oleic acid, a common impurity found in CLA, to trap electrons thus influencing the reaction kinetics significantly. The influence of terpolymer composition, chain transfer agent concentration, cross-linker concentration, molecular weight, viscosity and particle size on tack, peel strength and shear strength was investigated by using a constrained mixture design. The final forms of the resulting empirical models allowed the creation of 3D response surfaces for PSA performance optimization. The incorporation of 30 wt.% CLA into a practical PSA application suitable for the removable adhesives category was achieved.

Valproic acid (VPA) is a broad spectrum antiepileptic agent used widely in the treatment of absence and tonic-clonic seizures. VPA is extensively metabolized and forms 17 metabolites in man. A monounsaturated metabolite, (E)-2-ene VPA, is at least as potent as the parent drug VPA in several animal models of epilepsy. Moreover, (E)-2-ene VPA appears to be free of two serious side effects of VPA, namely hepatotoxicity and teratogenicity. Another monounsaturated metabolite of VPA, 4-ene VPA, has been incriminated in the pathogenesis of fatal hepatic failure in children on VPA therapy. This thesis describes the synthesis of (E)-2-ene VPA and 4-ene VPA and the development of a simple and sensitive capillary gas chromatographic-mass spectrometric (GCMS) assay method for the estimation of (E)-2-ene VPA and 4-ene VPA in the biological fluids of the rat. This thesis also describes the pharmacokinetics of (E)-2-ene VPA and 4-ene VPA at two dose levels of 20 and 100 mg/kg in normal and bile exteriorized rats. A simple capillary GCMS assay method was developed that involves a single extraction of 80 µL of plasma, urine or bile with ethyl acetate followed by derivatization with MTBSTFA (N-tertiarybutyldimethylsilyl-N-methyl-trifluoroacetamide). For an 80 µL biological sample employed for extraction, the lowest detection limit for (E)-2-ene VPA was 60 ng/mL and for 4-ene VPA, 100 ng/mL. The calibration curves for (E)-2-ene VPA were linear over a fairly wide concentration range of 0.4-35 /µg/mL in plasma and 2-200 µg/ml in urine of the rat. Standard curves for 4-ene VPA were prepared in concentration ranges of 0.5-45 µg/mL in plasma and 2-80 µg/ml in urine. The assay method is reliable, reproducible, and is able to separate the diene metabolites of (E)-2-ene VPA. For pharmacokinetic studies, a single intravenous (IV) bolus dose of either (E)-2-ene VPA or 4-ene VPA was administered to normal or bile-exteriorized rats. On increasing the dose from 20 to 100 mg/kg in normal rats, the apparent plasma clearance of (E)-2-ene VPA changed from 4.9 ± 1.7 (SD) to 3.0 ± 0.3 mL/min.kg, and of 4-ene VPA decreased from 8.7 ± 0.6 to 5.9 + 0.5 mL/min.kg. A total (conjugates and unconjugates) of 32 + 6% of the low dose and 50 ± 11% of the high dose of (E)-2-ene VPA was recovered in the urine of the rat. The second metabolite, 4-ene VPA, was eliminated in the urine to a relatively smaller extent (22 ± 3% of the low dose and 28 ± 6% of the high dose). In bile-duct cannulated rats, the apparent plasma clearance of (E)-2-ene VPA was 7.7 ± 1.8 mL/min.kg at the low dose and 6.0 ± 1.1 mL/min.kg at the high dose. The corresponding values for 4-ene VPA were 11 ± 1.8 mL/min.kg and 7.4 ± 1.1 mL/min.kg, respectively. The apparent elimination half-life of (E)-2-ene VPA remained unchanged at 20-21 min at the two dose levels, compared to a 1.5 fold increase in the t½ °f 4-ene VPA from 13 ± 2 to 19 ± 3 min. The fraction of the low dose (29 ± 5%) eliminated in bile was significantly larger than at the high dose (21 ± 4%), when calculated as the sum of conjugated and unconjugated 4-ene VPA. The biliary elimination of (E)-2-ene VPA showed a non-significant change from 38 ± 10 to 31 ± 9% on increasing the dose. Like the parent drug VPA, (E)-2-ene VPA and 4-ene VPA showed enterohepatic recirculation in the rat which produced secondary plasma peaks in normal animals. Moreover, both (E)-2-ene VPA and 4-ene VPA showed a rapid but transient choleretic effect in the rat. The plasma protein binding of 4-ene VPA was apparently low (14-25%), in the concentration range of 20-350 µg/mL. The results indicate that 4-ene VPA is cleared much faster from the plasma than (E)-2-ene VPA in the rat. The plasma levels of 4-ene VPA required to show a non-linear decline (>200 µg/mL) in the rat are two orders of magnitude higher than 4-ene VPA levels (<1 µg/ml) seen in patients on VPA therapy. It is, therefore, unlikely that 4-ene VPA is eliminated more slowly than VPA in man. On the other hand, the plasma elimination t½ of (E)-2-ene VPA in bile-exteriorized rats is longer than that reported for VPA, indicating that (E)-2-ene VPA may have a longer lasting pharmacologic effect than VPA. / Pharmaceutical Sciences, Faculty of / Graduate

Selenenic acids and other organoselenium compounds are important both in organic and biochemistry. In organic chemistry, syn-elemination of selenoxides is used to prepare alkenes, giving a selenenic acid by-product. In biochemistry, selenocysteine is catalytically active in a variety of selenoenzymes, which have antioxidant properties, and is oxidized to a selenenic acid intermediate. For example, glutathione peroxidase (GPx) plays a role in fighting oxidative damage by catalyzing the reduction of hydroperoxides. Previous studies have shown that the lighter chalcogen analogue of selenenic acid, sulfenic acid, is a powerful antioxidant and that the known antioxidant activity of garlic is attributable to the 2-propenesulfenic acid derived from the compound allicin. This has prompted questions concerning the role of selenenic acid in the antioxidant activity of organoselenium compounds. In order to study the physiochemical properties of selenenic acids –a functional group about which little is known—and to evaluate their potential as antioxidants, a persistent selenenic acid is needed. Herein, the model compound, 9-triptyceneselenenic acid, is prepared by a previously reported procedure and a new pathway is designed, such that its properties and reactivity can be studied. The oxidation of thiols is important in cell signalling, leading to the disulfide bonds implicated in post-translational modification, among other biological roles. While this reaction is presumed to occur through the reaction of thiol with an oxidant that forms sulfenic acid, and from a subsequent reaction of sulfenic acid with another thiol, sulfenic acids are so reactive that they are not usually seen as intermediates. Given the stability of the 9-triptycenesulfenic acid previously synthesized, preliminary kinetic study of the oxidation of 9-triptycenethiol to its corresponding sulfenic acid is made possible.

Modifications to the GCMS assay for valproic acid and 12 metabolites were attempted with respect to internal standards and derivatizing reagents. Four new internal standards, octanoic acid and 2-methylglutaric acid for analysis of VPA and metabolites and hexanoic acid and di-ռ-butylacetic acid for the analysis of hexadeuterated VPA and metabolites were used. Two new derivatizing reagents, MSTFA and MTBSTFA, were tested as alternatives to the reagent previously used. TMS (MSTFA) and tBDMS derivatives were compared with respect to sensitivity, stability, and chromatographic time. The derivatives formed from MTBSTFA were extremely stable a major drawback was the formation of a diderivative of 3-keto VPA upon increased heating time and storage. Preliminary data on the metabolism of D₆-VPA was obtained in one volunteer. The substitution of six deuterium atoms for six hydrogen atoms resulted in an isotope effect with decreased serum trough concentrations of 4-ene VPA and 2,4-diene VPA. Valproic acid and carbamazepine are frequently coadministered in efforts to optimize seizure control. VPA is extensively metabolized while CBZ is known to induce the hepatic microsomal enzyme system, and thus, this is a potentially toxic interaction. Pharmacokinetic parameters for VPA were obtained before and after CBZ administration in five, healthy male volunteers. Increased plasma clearance of VPA accompanied by decreased plasma concentrations, serum half-life, and AUC values were observed after CBZ comedication. This was consistent with the ability of CBZ to induce the hepatic microsomal enzyme systems in a manner similar to phenobarbital. Serum trough and steady state concentrations and AUC values for 12 metabolites were determined before and after CBZ administration. The AUC values for the monounsaturated metabolites decreased after CBZ administration while the AUC values of the polar metabolites increased. The amount of 4-ene VPA, a potential hepatotoxin, was not increased in the serum after administration of CBZ. The amounts of the two diunsaturated metabolites, 2,3'-diene VPA and 2,4-diene VPA, were increased in the serum of the volunteers after CBZ administration. The amount of 2-ene trans VPA in the serum was significantly decreased after CBZ administration, while the amount of 3-keto VPA did not increase. Urinary metabolic profiles were determined individually and grouped in pathways for the five volunteers before and after CBZ administration. Increased recoveries of 4-ene VPA, 4-keto VPA, and 2-PSA after CBZ administration were consistent with enhanced ω-1 oxidation. Formation clearance, metabolic clearance, and fraction metabolized were determined for the metabolic pathways and for the individual metabolites. CBZ adminstration resulted in increased formation clearances for all pathways. The results obtained from this study indicate that CBZ caused a general induction of VPA metabolism and did not specifically affect a particular pathway. The effect of CBZ on the beta-oxidation pathway is not clearly understood. CBZ may cause a metabolic shift away from beta-oxidation, or actually inhibit beta-oxidation to some extent. As well, peroxisomal beta-oxidation may be involved. / Pharmaceutical Sciences, Faculty of / Graduate