Graduation date: 2001

Graduation date: 1997

Graduation date: 1993

Graduation date: 1991

Graduation date: 1992

Graduation date: 1993

Some antibiotics, including co-trimoxazole, inhibit warfarin’s metabolism and may be associated with greater risk of hemorrhage in warfarin-treated patients. This thesis examines the risk of upper gastrointestinal (UGI) hemorrhage in older patients receiving warfarin and antibiotics commonly used to treat urinary tract infections, with a focus on co-trimoxazole. This population-based nested case-control study using Ontario healthcare databases, identified residents aged 66 years or older continuously on warfarin (n=134,637). Cases were those hospitalized with UGI hemorrhage (n=2151). Cases were nearly 4 times more likely than controls to have recently received co-trimoxazole (adjusted odds ratio (OR), 3.84; 95% confidence interval (CI) 2.33 – 6.33). Ciprofloxacin was also associated with an increased risk (adjusted OR 1.94; 95% CI 1.28 – 2.95), but no significant association was observed with amoxicillin, ampicillin, nitrofurantoin or norfloxacin. Among older patients receiving warfarin, co-trimoxazole is associated with a significantly higher risk of UGI hemorrhage than other commonly used antibiotics.

Some antibiotics, including co-trimoxazole, inhibit warfarin’s metabolism and may be associated with greater risk of hemorrhage in warfarin-treated patients. This thesis examines the risk of upper gastrointestinal (UGI) hemorrhage in older patients receiving warfarin and antibiotics commonly used to treat urinary tract infections, with a focus on co-trimoxazole. This population-based nested case-control study using Ontario healthcare databases, identified residents aged 66 years or older continuously on warfarin (n=134,637). Cases were those hospitalized with UGI hemorrhage (n=2151). Cases were nearly 4 times more likely than controls to have recently received co-trimoxazole (adjusted odds ratio (OR), 3.84; 95% confidence interval (CI) 2.33 – 6.33). Ciprofloxacin was also associated with an increased risk (adjusted OR 1.94; 95% CI 1.28 – 2.95), but no significant association was observed with amoxicillin, ampicillin, nitrofurantoin or norfloxacin. Among older patients receiving warfarin, co-trimoxazole is associated with a significantly higher risk of UGI hemorrhage than other commonly used antibiotics.

More than 30 members of the diverse amphidinolide family of biologically active macrolides have been isolated over last three decades. From this family, amphidinolides C and F stand among the most complex and densely functionalized affiliates. Recently, we have accomplished the first total synthesis of amphidinolide F. The all-carbon framework of amphidinolide C has been synthesized. During endeavor toward the total syntheses of amphidinolides F / C, we have uncovered a "hidden symmetry element" present in the northern and southern domains of amphidinolides F / C. The southern C₁-C₈ and northern C₁₈-C₂₅ tetrahydrofuran segments were derived from a common intermediate. A scalable silver-catalyzed isomerization / cyclization on propargyl-benzoate / diol furnished the common intermediate in multigram quantity. The common intermediate provided access to over half of carbon backbone of the macrocycle as well as majority of stereochemistry present in amphidinolides F / C. Two strategically different techniques have been developed for the C₉-C₁₁ diene preparation. A metal-catalyst free Weinreb amide-vinyl lithium coupling / methylenation sequence furnished the diene motif. Alternately, diastereoselective addition of a dienyl iodide derived 2-lithio-1,3-diene species to an α-oxy aldehyde installed the C₉-C₁₁ diene and secured the C₈ stereochemistry in single operation. The dienyl iodide was prepared via a regioselective hydrostannylation on an enyne. A challenging alkylation between an α-branched sulfone and an α-silyloxy iodide generated the all-carbon frameworks of amphidinolides F / C. An efficient oxidative desulfurization incorporated the carbonyl moiety at C₁₅. The protecting group on C₁₈ alcohol was found to have significant effect on the sulfone-iodide alkylation / oxidative desulfurization sequence. Installation of chelating ethoxyethyl ether on C₁₈ alcohol helped the successful incorporation of C₁₅ ketone and solved the deprotection problem in advanced stage of synthesis. A detailed analytical and computational study on proline sulfonamide-catalyzed aldol reactions has been performed. The pKa value of a proline sulfonamide catalyst was determined experimentally via NMR titration technique. Computational study revealed the origin of enhanced stereoselectivity by proline sulfonamide catalysts over parent proline. The non-classical hydrogen bonding interactions were found to be responsible for improved diastereoselectivity. / Graduation date: 2013

Graduation date: 1991