Typescript (photocopy) / iv, 201 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.) Dept. of Organic Chemistry, University of Adelaide, 1981

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

Thesis (Ph.D.) Dept. of Organic Chemistry, University of Adelaide, 1981. / Typescript (photocopy).

Thesis (doctoral)--Nijmegen, 1982.

Thesis (M.D.)--University of Hong Kong, 1982. / Also available in print.

Nifedipine is a photolabile calcium channel antagonist which undergoes rapid photodegradation in solution and in solid-state with an accompanying loss of pharmacological potency and clinical efficacy. Nifedipine photostabilization which has received considerable attention has principally been achieved by physical obscuration and through the use of colourants or ultraviolet light absorbers incorporated into liquid preparations, translucent packaging materials, gelatin capsules and/or their fillings and tablet coatings or cores. This study was initiated by a South African pharmaceutical manufacturer in response to increasing evidence that cyclodextrin (CD) inclusion complexation may improve drug photostability. The brief was to evaluate the potential of selected cyclodextrins as photoprotecting agents for nifedipine in the solid-state. Areas of investigation included i) quantitative method development and validation for selective determination of nifedipine, ii) phase solubility studies to establish the solubilizing potential and complexing tendencies of selected cyclodextrins, iii) preparation of solid-state nifedipine - cyclodextrin binary systems using an industrially applicable method, iv) pre-formulation photostability studies to determine the effects of the cyclodextrins on solid-state nifedipine photostability and v) comparative in vitro dissolution assessments of nifedipine, the nifedipine - cyclodextrin binary systems and their respective physical mixtures. Phase solubility studies demonstrated that soluble nifedipine - cyclodextrin complexes were formed in aqueous solution, but the magnitude of the interactions were generally low as reflected by the calculated stability constants which decreased in the rank order, heptakis (2,6-dimethyI)-β-CD (DM-β-CD) > randomly methylated-β-CD (RM-β-CD) > β-CD ≈ 2-hydroxypropyl-β-CD (2HP-β- CD) > γ-CD ≥ 2-hydroxypropyl-γ-CD (2HP-γ-CD). An industrially applicable kneading method yielded binary systems with spectral and thermal characteristics similar to the respective physical mixtures, implying weak solid-state inclusion complexation. Preparation of an amorphous nifedipine - RM-β-CD product using a heating method is reported. A 1.7- and 1.9-fold improvement in solid-state nifedipine photostability was observed for I : 1 molar ratio β-CD and γ-CD kneaded products, respectively, when exposed to window-filtered daylight and could be attributed to changes in opacity of the crystalline kneaded products. The remaining cyclodextrins produced negligible nifedipine photostabilization. Nifedipine in vitro dissolution was improved considerably from γ-CD and RM-β-CD .kneaded products as a result of increased nifedipine wettability, solubility and reduced particle size. iii

Glyphosate, a non-selective herbicide, is antagonized by salts in the spray carrier and responds to surfactant type and concentration. Glyphosate antagonism by dissolved salts such as calcium and magnesium was verified with natural water carriers and with carriers to which salts were added. Salt antagonism of glyphosate occurred from the formation of complexes that were less absorptive than the formulated isopropylamine glyphosate. Absorption of various salts of glyphosate varied as follows: isopropylamine > acid > ammonium > sodium > calcium. Ammonium sulphate increased the absorption of glyphosate both in distilled water carriers and in water carriers containing calcium chloride. Absorption and retention of glyphosate generally increased as surfactant (nonylphenol ethoxylate) hydrophilic/lipophilic balance (HLB) increased. The optimal HLB for glyphosate absorption was lower when ammonium sulphate was added to the spray carrier. An experimental adjuvant (trade name: Power-Up) that contained nonionic surfactant and ammonium sulphate, increased glyphosate efficacy more than the currently registered South African adjuvants. This could be as a result of increased foliar absorption and/or retention on foliage. The use of acid containing adjuvants was not essential for adequate glyphosate efficacy. Visual assessment of spray droplet residuals on leaves indicated that the appearance of spray droplet residuals was linked to glyphosate efficacy. Thick, amorphous and grainy spray droplet residuals on the leaf surface was an indicator of poor efficacy, whilst thinner, smoother residuals in close contact with the leaf surface was linked to increased efficacy. / Thesis (PhD (Agronomy))--University of Pretoria, 2005. / Plant Production and Soil Science / unrestricted

Toxicities of sulfur-based drugs have been attributed to formation of highly reactive sulfur oxo-acids and depletion of glutathione by the formation of reactive metabolites. Metabolic activation of these sulfur centers to conceivably toxic reactive metabolites (RMs) that can covalently modify proteins is considered the initial step in drug-induced toxicity. Despite considerable effort and research, detection and characterization of these RMs during drug development and therapy remains a challenge. Methimazole (MMI) and 6-propyl-2-thiouracil (PTU) are two commonly used antithyroid, sulfur-based drugs. Though effective, these drugs are associated with idiosyncratic toxicity. PTU has acquired a black box warning and physicians are calling for its withdrawal. RMs resulting from bioactivation of these drugs have been implicated in the aforementioned adverse reactions. Unfortunately, isolating and detecting RMs using traditional analytical techniques has not been successful due to their high reactivity and short life span, typically less than a minute. Current approaches in drug metabolism studies use microsomal incubations to generate RMs, which are then trapped using nucleophiles. Antithyroid drugs, however, are known to deactivate enzymes involved in their oxidation. Moreover, due to the complex nature of biological matrices and low abundance of possible toxic conjugates, this technique results in poor selectivity and sensitivity. This study developed and optimized an analytical method based on coupling electrochemical redox reactions and mass spectrometry to generate, detect and identify RMs from antithyroid drugs. The metabolites were also compared to those that were generated using chemical oxidants and biological microsomes. Mimicry of enzymatic oxidation of the antithyroid drugs was carried out by electrochemically oxidizing them using a coulometric cell coupled on-line to electrospray ionization mass spectrometry (EC/ESI-MS). Oxidation of MMI and subsequent trapping with nucleophile resulted in formation of adducts with N-acetylcysteine, revealing reactive metabolites. The most-postulated metabolite, sulfenic acid, had never been isolated or detected until now, using electrochemistry on-line with electrospray ionization. The results showed that bioactivation of MMI proceeds predominantly through the S-oxide and not through formation of thiyl radicals. These same trapping experiments were also conducted with PTU, but no conjugates were detected. The lack of conjugates from PTU does not preclude formation of RMs, but asserts radical pathway might be dominant in EC oxidation. A double mixing stopped flow was used to investigate the kinetics and mechanism of reaction of the MMI and the biologically relevant hypochlorous acid (HOCl), a product of oxidation of chloride (Cl-) ions by myeloperoxidase. The products from the chemical oxidations were compared to the electrochemically generated metabolites, some differences were apparent. Human liver microsomes (HLM) were also used, to investigate oxidation of PTU. Oxidation of PTU, resulted in the supposedly toxic S-oxide, but this has never been isolated, save for speculation. A comparison of metabolites that were found with HLM to those generated electrochemically showed some degree of similarity. These results show that in vitro techniques such as chemical oxidations and electrochemistry coupled to mass spectrometry can be used to mimic oxidative metabolism and subsequent high throughput screening of reactive metabolites.

A procedure was developed to determine the effect of a dopamine (DA) antagonist (haloperidol) and a DA agonist (d-amphetamine) on rats' perceptions of the hedonic value of food. Eighteen rats were trained to discriminate between two quantities of sweet food pellets (1 and 4), in a forced-choice two-lever successive discrimination procedure. To control for non-specific perceptual effects of the treatments, the rats were also trained to discriminate between 1 and 4 tones. It was established that rats attended to the value of food, as well as the proportional differences in quantity, when discriminating food quantities. This was accomplished by altering the value of the food in two ways. Firstly, "hunger" was altered by changing the degree of food deprivation during testing. Secondly, unsweetened food pellets were introduced as probe cues. These two methods of altering the value of food pellets were utilized while quantity generalization gradients were determined, by presenting animals with 1,2, 3 and 4 numbers of stimuli as probe cues. Two measures were derived from these generalization gradients: the point of subjective equality (PSE), which is the calculated number of stimuli that would maintain responses equally distributed between the two levers, and the slope of the gradient. The PSE primarily reflects perceptual processes, while the slopes of the gradients provide an index of performance impairment. It was observed that decreasing the value of food by either decreasing food deprivation or reducing the sweetness of the food pellets resulted in the rats perceiving a given quantity of food as larger than before these treatments (decreased the food PSE). Neither altering food deprivation nor introducing novel tone probes had an effect on the numerical attributes of tones, as reflected by the tone PSE. Haloperidol (0.030, 0.50 and 0.083 mg/kg, i.p.) produced a statistically significant, but slight dose-dependent performance deficit, as reflected by the slope of the generalization gradients. It did not affect the perception of food pellet quantities at any dose, as reflected by the food PSE. Haloperidol decreased the number of tones a given quantity was perceived as by rats (increased the tone PSE). Amphetamine (0.25, 0.50 and 1.0 mg/kg, i.p.) decreased the perception of a given quantity of food (increased the food PSE) in a dose-dependent manner, without a significant effect on performance. Thus, amphetamine enhanced the hedonic value of food. Amphetamine also increased rats' perceptions of a given number of tones (decreased the tone PSE). It therefore appears that while d-amphetamine can enhance the perceived hedonic value of food, haloperidol has no effect on rats' perceptions of the hedonic value of food. Furthermore, evidence that DA systems are involved in the mechanism of an "internal clock" or "counter" was obtained. / Medicine, Faculty of / Graduate

Antergan is one of the ethylenediamine type of antihistamines; in this work ten analogues of it were prepared. That pπ conjugation is essential to antergan's antihistaminic activity has already been established. Six of these analogues (A-l a-d, and B-l and 2, illustrated in Fig. 2 , p. 4 ) were synthesized in order that the significance of pπ conjugation in the antihistaminic properties of antergan molecule may at some future time be investigated. The problem is to find in what way alteration (i. e. , increase or decrease in) electronic density of the pπ -conjugated moiety of the molecule affects antihistaminic activity. The analogues A-l a-d involved ortho-, meta-, and para-methyl, and para-bromo substitution to the aromatic ring which gives rise to pπ conjugation in the antergan molecule; while the ring which gives rise to homo conjugation was replaced by a cyclohexyl moiety to eliminate any possible contribution of homoconjugation to antihistaminic activity. In analogue B-l, the antergan structure was modified so that the aromatic ring which gives rise to pπ, conjugation was removed from the rest of the molecule by a methylene group, i.e. , the phenyl group was replaced by a benzyl moiety. The other ring was left unmodified. Another compound (B-2) relocated the aromatic ring giving rise to pπ conjugation to the adjacent methylene carbon, so that pπ conjugation was eliminated; this compound is the nitrogen analogue of diphenhydramine and thiodiphenhydramine. In order that the importance of homo conjugation to antergan's antihistaminic activity may be established, the aromatic ring which gives rise to pπ, conjugation was replaced by a cyclohexyl moiety (A-3). Two compounds were synthesized in which the aromatic ring giving rise to homoconjugation were replaced by 3-cyclohexyl moieties (A-2a and b); while the aromatic ring which gives rise to pπ, conjugation was left unaltered in one of the compounds (b) and replaced by a cyclohexyl moeity in the other (a). In the tenth compound (A-1 e), both aromatic rings giving rise to both homo- and pπ - conjugation were removed and replaced by cyclohexyl moieties. The resulting analogue of antergan has already been demonstrated to have a very low antihistaminic activity compared to diphenhydramine, but it was felt that it would provide a useful comparison for the antihistaminic activities of the other antergan analogues prepared in this work. Two final intermediates in the synthesis of other analogues of antergan were prepared. In these analogues (C-2a and b) the aromatic ring giving rise to homoconjugation would have been replaced by the 1-cyclohexenyl moiety, while the other aromatic ring which gives rise to pπ conjugation would have been the same in one of the analogues, and replaced by a cyclohexyl moiety in the other. In intermediates of analogues D-l and 2, the ring giving rise to homoconjugation would have been replaced by 2, 5- and 1,4-cyclohexadiene respectively, while the aromatic ring giving rise to Pπ conjugation was replaced by the cyclohexyl moiety. In intermediates D-3 and 4, the aromatic ring giving rise to homoconjugation would have been replaced by cyclohexyl, while the aromatic ring giving rise to pπ, conjugation would have been replaced by 2, 6-dimethylphenyl and 3-cyclohexenyl moieties. / Pharmaceutical Sciences, Faculty of / Graduate