Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 6 uppsatser. Publikationen felaktigt numrerad: 805.

Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 6 uppsatser.

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 140-153). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph. D.)--Florida State University, 2005. / Advisor: Dr. John G. Dorsey, Florida State University, College of Arts and Sciences, Dept. of Chemistry and Biochemistry. Title and description from dissertation home page (viewed Sept. 19, 2005). Document formatted into pages; contains xxii, 154 pages. Includes bibliographical references.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2003. / Härtill 6 uppsatser.

Propafenone is a new class 1C antiarrhythmic agent with additional calcium antagonistic and beta-blocking activities. Clinically it is effective in the treatment of supraventricular and ventricular tachycardia, atrial and ventricular fibrillation, ventricular premature contractions and for the management of Wolf-Parkinson-White syndrome. In North America it is still an investigational drug. Propafenone is a chiral drug and is used clinically in the racemic form. The enantiomers of numerous chiral drugs have been shown to differ in their disposition kinetics in the body due to their stereoselective pharmacokinetics and/or pharmacodynamic properties. Two enantiomers are thus often considered as two different entities. The relative antiarrhythmic activities of individual enantiomers of propafenone have not been studied, nor their pharmacokinetic parameters have been elucidated. In order to study the possible enantioselective role of propafenone in the body, a stereoselective assay method would be required. The present study describes the development of a sensitive and stereoselective chromatographic assay method for the simultaneous determination of the two enantiomers of propafenone in human plasma. Attempts for direct separation of the enantiomers of propafenone included several GLC and HPLC chiral stationary phases. The chiral stationary phases were a Chirasil-Valʳ GLC stationary phase, a Pirkle 2,4 dinitro-(D)-phenylglycine HPLC stationary phase and a β-cyclodextrin HPLC stationary phase. Unfortunately, these did not resolve the enantiomers of propafenone. Formation of the diastereomers with R(+)-⍺-methyl benzyl isocyanate and racemic propafenone were partially resolved on a reverse phase HPLC using a 5 u, 25 x 0.45 cm i.d. ODS column and methanol/water (70:30) as the mobile phase. However, due to the long retention time (42 min), incomplete resolution (RS=1.15) and poor sensitivity for detection (500 ng of each enantiomer injected) this method was not deemed suitable for the pharmacokinetic studies planned, since the therapeutic plasma concentration range of propafenone is 64-1044 ng/mL. The second chiral derivatizing reagent, 2,3,4,6-tetra-0-acetyl-β-D-glucopyranosylisothiocyanate (GITC), was synthesized in our laboratory. This reagent gave better resolution of the enantiomers (RS=1.4) within 15 minutes with enhanced sensitivity for detection (150 ng of each enantiomer injected). To further optimize the limit of detection for future pharmacokinetic studies of propafenone, R(-)-1 -(naphthyl) ethylisocyanate, a chiral derivatizing agent, was employed. This reagent reacted with racemic propafenone and permitted the resolution of both enantiomers within 24 minutes (R5=l.25) and the minimum level of detection was 100 ng (at the detector) for each enantiomer of propafenone. Using this method, linearity was established over the concentration range, 125-1000 ng for each enantiomer (injected) with a coefficient of determination (r²) of greater than 0.99. Reproducibility and precision of this assay method was obtained with an average coefficient of variability of 4.5% for the R(-) enantiomer and 7.2% for S(+) enantiomer at concentrations of 125-1000 ng/mL. Below the lower quantity, the NEIC-propafenone reaction virtually stopped at the conditions set for derivatization. A similar lack of reactivity at low concentrations was also observed with the GITC-propafenone reaction. The absence of an autocatalysing effect of propafenone at lower nanogram levels, as well as two possible conformational forms of propafenone were also investigated. The existence of two conformational isomers of propafenone, due to intramolecular hydrogen bonding in aprotic solvents, was chromatographically verified. In addition, chromatographic separation of all the proposed conformers was obtained, indicating that enantiomeric separation and quantitation of propafenone enantiomers as their urea derivatives is substantially hindered. To eliminate hydrogen bonding interactions, the carbonyl group of propafenone was blocked with dansylhydrazine and subsequently derivatized with the chiral R(-)NEIC reagent. The HPLC resolution (RS=1.35) of this dual derivative was better than that using the R(-) NEIC reagent alone, and the minimum level of detection was 2.5 ng for each enantiomer. Unfortunately, this procedure still did not provide adequate assay precision and accuracy at the lower levels required for single dose pharmacokinetic studies. / Pharmaceutical Sciences, Faculty of / Graduate

Thesis (Ph. D.)--Florida State University, 2004. / Advisor: Dr. John G. Dorsey, Florida State University, College of Arts and Sciences, Dept. of Chemistry and Biochemistry. Title and description from dissertation home page (viewed June 16, 2004). Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 87-123).

Thesis (doctoral)--University of Göteborg, 1994.