Thesis (Ph. D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2007. / "A dissertation in pharmaceutical sciences and chemistry." Advisor: Ashim K. Mitra. Typescript. Vita. Description based on contents viewed July 16, 2008; title from "catalog record" of the print edition. Includes bibliographical references (leaves 154-179). Online version of the print edition.

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The solution structure determination of DNA molecules has been an important part of structural biology. NMR solution structures are a complement to structures solved via X-ray crystallography; the two methods are the only ways of obtaining three dimensional coordinates of macromolecules. Because of the nature of the molecule, the solution structure determination of DNA has been a challenging task. Assignments are the first and most important part of NMR structures, and can be simplified for DNA with the use of the rotating frame Overhauser spectroscopy (ROESY) experiment. The ROESY technique can be used for unambiguous assignments of H2' and H2" protons and for distinguishing the three main forms of DNA duplexes: A-form, B-form and Z-form. Many types of DNA have been examined using NMR spectroscopy, including drug-bound DNA complexes. Most previous studies of complexes of the anti-cancer drug Actinomycin D (ActD) and DNA used self- complementary sequences to identify stabilizing features. The studies presented in this thesis use non-self-complementary DNA hexamers to identify the two orientations in the binding of the asymmetric ActD drug. The largest preference of asymmetric binding was found for the d(CCGCCG)•d(CGGCGG) sequence; however, NMR spectral complications prevented the structure elucidation of this complex. Instead the solution structure was determined for the complex with the next largest orientational preference, ActD:d(CTGCGG)•d(CCGCAG), which has 67% of ActD molecules intercalated with the benzenoid side of ActD in the first strand. The solved structure identifies unusual DNA features, which could be due to the bound drug inducing structural changes to the B-DNA duplex or the presence of conformational motion. For seven of the eight sequences, the orientation of ActD intercalation within the DNA duplex was identified. The largest preference occurs when the benzenoid intercalation site is followed by a guanine. When this guanine is replaced by an inosine, a reduction in the asymmetric binding of ActD is observed, indicating that the guanine NH₂ group plays a role in the intermolecular contacts. Thus, the two orientations of ActD binding are not present in equal concentrations although their structures are similar, and the preference of orientation is influenced by the asymmetric DNA sequence flanking the intercalation site. / Graduation date: 2002

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Thesis (Ph. D.)--University of Wisconsin--Madison, 1974. / Typescript. Vita. Description based on print version record. Includes bibliographical references (leaves 147-152).

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2006. / Title from title screen (site viewed Aug. 1, 2007). PDF text: 1 v. : ill. Includes bibliographical references. Also available in microfilm and microfiche formats.

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.

Phenobarbital pretreatment, in man and rat, has been observed to decrease the plasma levels attained after administration of solid dosage forms of griseofulvin. Various mechanisms including induced metabolism, increased gastrointestinal motility, diminished dissolution rate or a complex mechanism involving enzyme induction, first-pass metabolism and distribution rate-limited elimination of griseofulvin have been suggested. This present investigation was initiated in an attempt to clarify the mechanism of this interaction. Intravenous administration of griseofulvin in control and phenobarbital dosed rats confirmed that no obvious differences existed in griseofulvin metabolism under the experimental conditions. The influence of gut motility on the absorption of griseofulvin administered as single oral doses of either 100 mg/kg in 0.5% Tween 80 (suspension) or 50 mg/kg in 100% polyethylene glycol (PEG) 600 (solution) was evaluated by pretreating rats with single intraperitoneal doses of either 10 mg/kg metoclopramide hydrochloride or 5 mg/kg propantheline bromide two hours prior to griseofulvin administration. Metoclopramide pretreatment accelerated the absorption rate of griseofulvin suspension (the time of peak-plasma level, Tmax was shortened from 6 to 3 hours) but reduced its total absorption by 50%. Conversely, this treatment regimen increased the total absorption of griseofulvin by 230% when administered in solution form. Propantheline preadministration, however, retarded the absorption rate (Tmax prolonged from 6 to 19 hours) but increased the total absorption of a suspension of griseofulvin by 50% The propantheline treatment regimen elicited a sharply contrasting effect by decreasing the total absorption (23%) of griseofulvin when given in solution form. It was therefore, concluded that a) the interaction of griseofulvin with metoclopramide and propantheline is formulation-dependent and b) the gut motility has a significant influence on the absorption of griseofulvin. The interaction between griseofulvin and phenobarbital was evaluated by administering single oral doses of a) suspension of 100 mg/kg griseofulvin in either 0.5% or 2% Tween 80, b) suspensions of 20 or 100 mg/kg griseofulvin in 70% PEG 300, or c) solutions of 50 mg/kg griseofulvin in 100% PEG 600. Test rats received single oral doses of 15 mg/kg sodium phenobarbital 24 hours prior to griseofulvin administration. The treatment reduced the total absorption of griseofulvin administered in 0.5% Tween 80 by 50%. The extent of the interaction was reduced to an insignificant level on increasing the concentration of Tween 80 from 0.5% to 2%. Phenobarbital did not alter the apparent rate of griseofulvin absorption since the peak plasma concentrations were coincident between control and test animals. Phenobarbital treatment did not affect the availability of griseofulvin when administered as suspensions or solutions in PEG as reflected by equivalent areas under the plasma curves at the same dose level in test and control animals. It can therefore be concluded that the interaction between griseofulvin and phenobarbital in the rat is a) a formulation-dependent phenomenon and b) not caused by either enzyme induction or an increased gut motility. It is concluded that when griseofulvin is administered as a suspension in 0.5% Tween 80 the phenobarbital-griseofulvin interaction in the rat is caused by a complex mechanism resulting in a diminished dissolution rate and subsequent decreased absorption. / Pharmaceutical Sciences, Faculty of / Graduate

Thesis (Ph. D.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains xvii, 122 p. : ill. Includes abstract. Includes bibliographical references (p. 46-53).

Class of 2012 Abstract / Objectives: To evaluate the literature with respect to drug-drug interactions of the hydroxymethylglutaryl CoA reductase inhibitors atorvastatin, fluvastatin, lovastatin, pitavastitin, pravastatin, simvastatin, and rosuvastatin with warfarin. Methods: This descriptive retrospective study identified articles reporting on each drug-drug interaction from the online databases PubMed (1970 – February 2012) and the drug compendia Micromedex and Facts & Comparisons. The studies included in this investigation were primary literature reports, written in English with human subjects. All studies included were evaluated using the van Roon 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions. This scale rates the study type from lowest to highest quality, from zero to four. Case-reports were evaluated 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: Twenty studies met the inclusion criteria. One study involved atorvastatin, four for fluvastatin, three for lovastatin, 2 for pitavastatin, 1 for pravastatin, 5 for rosuvastatin, and 6 for simvastatin. The mean van Roon quality of evidence score was 2.1+/- 0.74, the mean score for atorvastatin, pitavastatin, and pravastatin was 3, with the mean score of fluvastatin, lovastatin, rosuvastatin, and simvastatin was 2. 70% of the literature reviewed were case-reports or letters. Conclusions: The studies and reports supporting HMG-CoA reductase inhibitors and warfarin drug-drug interactions are most commonly case- reports and are of low quality and quantity.