This work presents research toward the total synthesis of the promising antibiotic lactonamycin and related polyketides specifically, a scalable, inexpensive, and universal process to access this family of natural products. Lactonamycin exhibits a wide range of promising biological activity. Most notable among these is the potent activity displayed against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Lactonamycin and each of the aforementioned structurally related polyketide natural products serve as good targets for synthetic efforts, particularly lactonamycin. Further impetus for total synthesis is provided by the interesting structural features of these related polyketides and the synthetic challenges associated with these features. The structure of lactonamycin contains several unique connectivities including a novel hexacyclic ring structure distinguished by a densely oxygenated DEF-ring system with three contiguous quaternary stereogenic centers. An approach to lactonamycin and its related polyketides has been developed, in particular two methodologies: (1) the tandem conjugate addition-Dieckmann condensation and (2) a quinone nitrile-oxide cycloaddition. These methods have allowed a unified approach to this class of biologically active natural products. The synthesis of the ABCD-ring system of lactonamycin has been accomplished in eleven steps by utilizing a novel tandem cyanide conjugate addition/Dieckmann condensation as a key step. This powerful annulation reaction was developed in a model system prior to application to the synthesis of the ABCD-rings of lactonamycin. Flexibility was observed in the nucleophile used to initiate the cyclization, holding promise for an application to the related polyketides tetracenomycin C, elloramycin, saintopin, saintopin E. This methodology has also allowed for a formal synthesis of tetracenomycin A2. Model studies on the highly oxygenated DEF-ring system were conducted. A high yielding, regioselective dipolar cycloaddition of a hydroxymethyl-substituted naphthoquinone with an appropriately substituted nitrile oxide was developed and implemented in the full ABCD-ring system of lactonamycin, providing rapid entry to an isoxazole intermediate possessing virtually all of the atoms necessary to construct the skeleton of lactonmycin. Diastereoselective installation of a final tertiary hydroxyl remained after [3+2] cycloaddition. Several methods geared toward solving this challenging synthetic problem are presented to better understand how it may be overcome. This dissertation describes a plan and progress toward lactonamycin that has allowed for the synthesis of a unique substrate where these methodologies may be utilized to complete the first total synthesis of lactonamycin.

No description available.

Although the pharmaceutical industry in Taiwan is not at large, there exist such two hundreds companies in this industry. In the past decade, such industrial development is unable to keep up with those of more developed countries, for instance, the United States and the United Kingdom. A few reasons behind such fact are due to the high barriers on research and development of the pharmaceutical industry. For those larger pharmaceutical companies, investments on research and development are continuously being attempted. Though such attempted level cannot be compared with those pharmaceutical industries from abroad, it serves as a fine learning model for other companies particularly those of smaller ones to take into considerations. The primary goal behind the study is to explore the development and research of the pharmaceutical industry. Furthermore, such finding could provide an important source for other companies and for the government in the future if they plan to develop such type of industry. In order to carry out the study, interview method suggested by the experts will be utilized. First and foremost, related documents and sources on the pharmaceutical industry field both including the developing and technical aspect will be collected. The major points will then be sorted and organized for further study. Next, those managers who specialize in this area will be interviewed; and their opinions and their methodological recognitions will then be analyzed. The study shows that most of these companies belong to the so called small and medium size enterprises. Their methods of modeling acquisition are decisions made by the top managers depending and according to the different situations and different cases. Most companies perceive some common factors like economical motivation, technical motivation and copyright and patent rights as the problems to be emphasized more. Finally, nine questions, comments and related discussion topics from the study are presented. In conclusion, this study suggests two aspects for further research. One is to analyze the feasibility on the possible integration of large-scale pharmaceutical companies in Taiwan and the second one is to develop policies for research and development of pharmaceutical industry. This is to further expand the purpose behind the research.

Thesis (M.S.)--Rutgers University, 2008. / "Graduate Program in Pharmaceutical Science." Includes bibliographical references (p. 41-42).

Thesis (Ph. D.)--University of Texas at Austin, 2002. / Supervisor: Kenneth A. Lawson. Vita. Includes bibliographical references. Also available from UMI.

Thesis (M.A.) -- Central Connecticut State University, 2009. / Thesis advisor: Joanne DiPlacido. "... in partial fulfillment of the requirements for the degree of Master of Arts in Psychology." Includes bibliographical references (leaves 103-114). Also available via the World Wide Web.

No description available.

This dissertation describes chemical investigations involving 11 Argentinean plant species and a sample of Chilean propolis. In total, 18 known and four novel compounds were isolated and identified. The compounds were tested in various antimicrobial assays. Three novel triterpenes, 3,4- seco-olean-12-en-3,28-dioic acid (4), 3alpha,-hydroxyolean-11-en-28,13 beta-olide (5), and 3alpha-hydroxyolean-11:13(18)-dien-28-oic acid ( 6) were isolated from the aerial parts of the Argentinean shrub, Junellia tridens (Lag.) Mold. (Verbenaceae). Another five compounds, oleanolic acid (1), oleanonic acid (2) and epioleanolic acid (3), all biosynthetically related to the three new oleananes, as well as epibetulinic acid (7) and sitosterol (8), were also isolated. LC-MS data are provided on the occurrence of these triterpenes in six other species of Junellia. We report the minimum inhibitory concentrations (MICs) of compounds 1--8 against Mycobacterium tuberculosis, and conclude that they are responsible for the antitubercular activity originally observed in the crude plant extract. Four other plants showing preliminary antitubercular activity were also investigated. The EtOAc extracts of Acantholippia seriphioides and Adesmia ameghinoi contained oleanolic acid (1) as their main constituent. The organic soluble portions of Chiliotrichium diffusum and Lathyrus magellanicus contained large amounts of ursolic acid (12) and sitosterol (8), respectively. Bioassay of the predominant compounds in these plants indicated that triterpenes were responsible for the antitubercular activity observed in the crude extracts. Fractionation of propolis (a product of honey beehives) from Colliguay in Central Chile led to the isolation, identification and bioassay of a novel gamma-lactone (14), five flavonoids (15--19), two diarylheptanoids (20--21), and a prenylated coumarin (22). All structures were elucidated primarily by 1D and 2D NMR and mass spectrometry. Based on the traditional use of propolis as an antimicrobial agent, the bioactivity of the purified compounds was determined against Staphylococcus aureus, Escherichia coli, Enterococcus faecium, and Candida albicans . Microscopic analysis of pollen present in the propolis provided clues to its botanical origins.

<p> Drug response is well documented to vary considerably among patient groups and populations, as well as within individual patients. Since drug prescribing is often based on population averages of drug response, many patients will not respond, and up to one-third may experience harmful toxicity. Genetics plays a large role in explaining the variability observed in response to different drugs and is an important factor driving precision medicine initiatives. Pharmacogenetic information can be useful in optimizing patient therapy, potentially reducing the cost of hospitalizations and treatment of adverse drug events. </p><p> As part of the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH), we analyzed 102,979 members of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort with genetic information available, along with almost two decades of electronic health record (EHR) data, prescription records, and lifestyle survey results. In one of the largest, most ethnically diverse pharmacogene characterization studies to date, we assessed cohort metabolizer status phenotypes for 7 drug-gene interactions (DGIs) for which there is moderate to strong evidence suggesting the use of pharmacogenetic information to guide therapy. 89% of the cohort had at least one actionable allele for the 7 DGIs in this study, and we observed large variations among ethnicities. Additionally, 17,747 individuals had been prescribed a drug for which they had an actionable or high-risk metabolizer status phenotype. For these individuals, the availability of pharmacogenetic information at point-of-care may have potentially led to a more personalized drug or dosing regimen. </p><p> Following this study, we assessed the utility of this resource for deriving two drug response phenotypes: weight gain induced by atypical antipsychotic use and major adverse cardiovascular events in clopiodgrel non-responders. Despite challenges in deriving phenotypes from the EHR, we were able to extract phenotypes that reflected observed estimates from previously published studies. Using these phenotypes, we performed candidate gene and genome-wide association studies to identify genetic variants associated with response. Altogether, this dissertation demonstrates the potential utility and clinical impact of integrating genetic data with EHRs for pharmacogenetic application and discovery, and provides the foundation for future studies in precision medicine.</p>

Bioavailability enhancement of poorly water soluble active pharmaceutical ingredients (API) is key for improving existing therapies and allowing for formulation of certain new chemical entities. The rate limiting step for absorption of these APIs is dependent on the dissolution rate and the APIs apparent solubility. Particle engineering processes such as evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) were developed to enhance API dissolution and bioavailbality through the production of amorphous and nanoparticulate API. The morphology, primary API domain size and miscibility of particles produced by EPAS and SFL were investigated by several complementary and novel techniques. It was found that the SFL composition displayed amorphous character, a primary danazol particle size of 30 nm and was consistent with a solid solution. The EPAS composition was mostly amorphous with slight crystallinity, a primary danazol particle size of 500 nm and was consistent with a solid dispersion. The ability of the nanoparticulate and amorphous particles to supersaturate dispersions and how this impacts oral bioavailability was tested through in vitro and in vivo models. Through the use of a testing method for supersaturation, it was found that EPAS and SFL compositions achieve higher apparent solubilities when compared to the physical mixture and commercial Danocrine® capsules. This improvement in solubility allowed for more danazol to be available for absorption in vivo. Pulmonary delivery of SFL nanoparticulate itraconazole was evaluated for pharmacokinetic parameters and steady state trough levels compared to oral delivery of an SFL oral composition and the commercial product. Inhalation of ITZ compositions is an effective method of antifungal therapy for the treatment and prophylaxis of invasive fungal infections. High and sustained lung tissue concentrations are achieved via inhalation of an amorphous ITZ pulmonary composition while maintaining serum levels which are above the minimum lethal concentration for A. fumigatus. Histology, macrophage uptake and IL-12 induction was evaluated for aerosolized amorphous ITZ nanoparticles. Pulmonary administration of amorphous ITZ nanoparticles or excipient placebo does not cause inflammation or changes in alveolar and airway histology. Uptake of ITZ by alveolar and airway macrophages occurs following inhalation of an amorphous ITZ composition. / text