published_or_final_version / Surgery / Master / Master of Surgery

Thesis (Ph. D.)--West Virginia University, 2007. / Title from document title page. Document formatted into pages; contains vi, 158 p. : ill. (some col.). Includes abstract. Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains xix, 227 p.; also includes graphics. Includes bibliographical references (p. 221-227).

Thesis (M.S.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 140-168) Also available in print.

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Class of 2011 Abstract / OBJECTIVES: To evaluate the quality of evidence in the literature substantiating major drug-drug interactions of the macrolide antibiotics azithromycin, clarithromycin, and erythromycin with digoxin, ergot alkaloids, and pimozide. METHODS: In this descriptive retrospective analysis, a list of articles reporting on each drug-drug interaction was compiled from the online databases Medline and International Pharmaceutical Abstracts, and the drug compendia Micromedex and Facts & Comparisons. The studies included in this analysis were primary literature reports, written in English, and consisted of human subjects. All studies included were evaluated using a 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions (van Roon scale). This scale rates the study type from lowest to highest quality, from zero to four. Case reports were additionally analyzed using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction. RESULTS: Thirty-seven studies met the selection criteria. There were 28 studies involving digoxin, two studies involving pimozide and seven studies involving ergot alkaloids. The mean quality of evidence score on the van Roon scale was 2.3 + 0.75, where digoxin studies had a score of 2.3 + 0.74, ergot alkaloids had a score of 1.9 + 0.38 and pimozide only had two studies with evidence scores of 2 and 4. Sixty-two percent of the studies reviewed were case reports. CONCLUSION: The reports substantiating some drug-drug interactions may be of low quality and few in number.

A number of 14-membered lactones, derived from 42 or 43 were used to investigate a series of alkylation, hydride reduction and hydrogenation reactions. These reactions yielded diastereoselective product distributions which were rationalized as proceeding through a [3434] conformation. A simple model for determining these low energy conformations was developed using MM2 calculations, energy trends of acyclic molecules, X-ray crystallography and NMR spectroscopy. In order to unambiguously identify ring conformations, a method to generate polar maps of the large ring lactones was developed. These polar maps quickly differentiated complex ring conformations as well as identifying the symmetry elements of a conformation. With the aid of polar maps, a new solid state conformation for 14-membered rings was discovered for two macrolides synthesized in this project. Furthermore, three additional unidentified examples of this conformation were recognized from the literature. Energy calculations showed this twisted conformation to be of very low energy. The discovery of the twist conformation led to an improved nomenclature for large rings which considers the number of bonds separating both corner and pseudo corner atoms. Under this proposed nomenclature, the twist conformation was designated the [34'3'4'] conformation. During this investigation, a useful technique for assigning the stereochemistry of E and Z-trimethylsilyl (TMS) enol ethers was developed using ¹H NMR nuclear Overhauser effect difference spectroscopy (NOEDS) experiments. One advantage of this technique over the widely used ¹³C NMR method is that only one isomer is required to accurately assign the Eor Z. stereochemistry. [Formula Omitted] / Science, Faculty of / Chemistry, Department of / Graduate

Le travail présenté dans ce manuscrit concerne la synthèse du fragment C12-C25 de la Thuggacine A, macrolide antibiotique, par deux voies de synthèse. La première voie de synthèse nous a permis de créer 4 des 5 centres stéréogéniques à partir du (R)-glycéraldéhyde acétonide. L'étape-clé d'induction asymétrique a montré que les 3 centres C18 à C20 présentent une configuration relative syn présente dans la Thuggacine A mais que les centres C17-C18 sont anti-configurés, configuration confirmée par cristallographie du composé 84. Les faibles rendements ainsi qu'un contrôle insuffisant de la diastéréosélectivité de ces 4 centres asymétriques nous ont conduit à étudier une stratégie de synthèse alternative. La deuxième voie de synthèse nous a permis d'obtenir le fragment C13-C25 en 10 étapes linéaires et avec un très bon contrôle de la stéréochimie des 5 centres stéréogéniques créés. Les 4 centres asymétriques C-17 à C-20 ont été construits grâce à deux réactions d'aldolisations type Evans, tandis que l'addition d'un allényl-stannane a permis l'introduction stéréosélective du centre C-16. / The herein presented study is concerned by the synthesis of the C12-C25 fragment of Thuggacine A, a potent antibiotic macrolide, through two distinct synthetic pathways. The first synthetic pathway enabled us to form 4 among 5 stereogenic centers from (R)-glyceraldehyde acetonide. The key induction asymmetric step showed that the 3 chiral centers C18-C20 were formed with a syn-configuration as in Thuggacine A and the C17-C18 stereocenters were anti-configurated, a result confirmed by X-ray cristallography of compound 84. Low yields and low diastereocontrol of these four chiral centers led us to envisage an alternative synthetic strategy. The second synthetic pathway enabled us ti obtain the C13-C25 fragment within ten linear steps and a high diastereocontrol of the five required stereogenic centers. The 4 chiral centers C-17 to C-20 were formed through two Evans's aldolization steps while the stereochemistry of the C16 center was secured by an allenyl-stannane homologation.

Thesis (M.S.)--University of Michigan, 1970.