<p> The aim of this thesis is to evaluate the impact of somatostatin receptor subtype-4 (SSTR4) actions on microglia cell viability, towards the understanding and advance of pharmacological treatments for Alzheimer&rsquo;s disease (AD). As of March 2016, there were 5 million people living in the United States with AD. Current drugs for AD have highly variable effects from patient to patient and are palliative at best. This thesis project focuses on the study of the BV2 cell line and the compound NNC 26-9100 (NNC). BV2 cells are immortalized microglial cells that maintain most of their morphology. The data collected suggests that BV2 cells can phagocytize amyloid-? peptides (A?), respond to lipopolysaccharide (LPS), and have the somatostatin receptor subtype-4 (SSTR4). NNC is a selective agonist of the SSTR4 and we have found that it causes BV2 cells to increase in number. The effects of NNC were able to be reduced with a somatostatin receptor pan-antagonist, cyclosomatostatin, and the adenyl cyclase activator forskolin. NNC can alter BV2 numbers by binding to the SSTR4, creating an intracellular cascade that results in the inhibition of adenyl cyclase and an increase in cell count. Collectively, a potential therapeutic mechanism for AD is increasing the number of microglial cells to increase both amyloid beta (A?) phagocytosis and degradation of A? by neprilysin.</p>

<p> The role of the professional nurse has evolved in numerous and unexpected ways since the founding of Nightingale&rsquo;s first school of nursing in 1860. One contemporary sphere in which nurses work is the biopharmaceutical and medical device industry, but little research exists regarding how the nurse engages with and experiences this role. </p><p> This qualitative, phenomenological study was undertaken to address the research question: What is the nature and process of the transition experience from a direct patient care role to a clinical research specialist role for the professional nurse? Two subquestions were also explored: What barriers and supports are encountered during the transition process? What facilitates successful work role transition from direct patient care to clinical research? </p><p> Ten professional nurses who had transitioned to industry based careers at least two years prior to this study were identified and selected via referral sources. Each nurse participated in a series of three in-depth recorded interviews. Through an iterative process of transcript review, coding, and thematic analysis, and utilization of Ashforth&rsquo;s (2001) ABCs of Role Identification and Nicholson&rsquo;s (1984, 2013) Work Role Transition Theory as lenses for interpretation, seven key themes emerged. These themes include: 1) I am alone: transition can be an isolating experience, 2) I am unprepared: transition requires mastery of unfamiliar skills and knowledge, 3) I am scared and sometimes overwhelmed: transition is associated with a lack of security, structure and balance, 4) I can do it: self-reliance and resourcefulness facilitate successful work-role transition, 5) I need to build new bridges: transition requires networking and support from others, 6) I am becoming: the transition experience can be empowering and offers opportunity for growth, and 7) I am still a nurse: nursing identity and values endure through transition. </p><p> This study offers several recommendations for further research to more deeply explore identified themes and ways to facilitate success in this work-role transition. In addition, using feedback from study participants, recommendations and suggestions are offered for nurse educators, professional nursing credentialing organizations, and to other nurses considering a career in the clinical research arena.</p>

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Medicine in Pharmaceutical Affairs Johannesburg, 2014 / Aim The first step in a wet granulation process is dry mixing. This step has the objective of ensuring that all the raw materials are mixed such that the end product is homogeneous. Dry mixing in a high shear mixer instead of a blender saves cost. However, the mixing parameters have not been well researched. Dry mixing parameters that are currently used, have been established through experience, trial and error and in-process testing. Alexander and Muzzio (2006) confirms this by stating that there are currently no mathematical techniques to predict blending behaviour of granular components without prior experimental work; therefore, blending studies start with a small-scale, try-itand- see approach. Even though they are referring to blending, the same is also true for dry mixing. Both processes are the mixing of powders. Therefore the aim of this research was to develop parameters for dry mixing, based on experimental work. Methods Using a Saral rapid mixer and wet granulator (Saral Engineering Company, India), experiments were performed according to a 24 two-level Plackett-Burman Design method, to determine the effects of different blades (mixer/impeller and chopper) speeds and mixing times on the homogeneity of the mixtures containing different ratios of two powders that have different densities and particle sizes. One of the powders mixed, was enalapril maleate. This was chosen as it can be assayed. Samples were taken from the bowl and tested for assay. The mix for a specific experiment is homogeneous if the results of all 7 assayed samples are within 10 % of the target % w/w value and the % Relative Standard Deviation (% RSD) of the 7 results is less than or equal to 5,0 %. The outcome was being measured in % RSD. A lower % RSD indicates a more homogeneous mix. The parameters developed, will be beneficial to pharmaceutical companies as it can assist them to improve accuracy, consistency and quality of granular mixes. The experimental method used can serve as an example for future experiments. Results The results indicated that impeller blade mixing speed and mixing time are the two factors that have the biggest impact on the homogeneity of a mix in a high shear mixer. Chopper blade speed was also found to be significant, but less than the above two parameters mentioned. Optimal parameters were predicted. Conclusion As there are many parameters to be controlled during dry mixing in a high shear mixer, a statistical design method is suitable to establish the parameters that would have the most impact on the end result. Statistically it was found that mixing speed of the main impeller and chopper blades and overall mixing time are the three factors that have the biggest impact on the homogeneity of a mixture. The mixing time and impeller blade speed have proven to be more significant than the chopper blade speed. Concentration was found to be insignificant. For our experiments and for the specific granulator used the following optimal parameters could be deduced: Impeller blade set at 191 rpm, chopper blade set at 2002 rpm and mixing time set at 3.01 minutes.

Thesis advisor: Tracy Regan / This study analyzes the response of pharmaceutical firms’ stock prices to the release of information regarding successful Phase III clinical studies and final FDA marketing approval. I employ an event study methodology to show that positive abnormal returns occur at these drug development stages, and that larger abnormal returns occur over a three-day window surrounding a sample of successful Phase III trial announcements in comparison to a sample of FDA approval announcements. To my knowledge, all previous literature of this kind has compared a random sample of firms making Phase III announcements to a random sample of FDA approval announcements. This study advances drug development literature by conducting a second set of event studies that compares the abnormal returns of the same drugs at the two drug development stages, and it finds that controlling for the unique characteristics of the drugs analyzed in event studies leads to a smaller difference in returns at the two drug development stages. The drugs selected for analysis were taken from IMS Health’s lists of the top 100 (or 200) best-selling pharmaceuticals from 2003 to 2010. They were split into 13 therapeutic classes, such as drugs for cardiovascular ailments and drugs for respiratory ailments. Regression analysis was conducted on the returns of the three-day window to find a positive relationship between the FDA approval of alimentary and cardiovascular drugs and stock price increases for larger pharmaceutical firms and the approval of nervous system drugs and stock price increases for smaller pharmaceutical firms. To my knowledge, this is the first study to show these relationships. / Thesis (BA) — Boston College, 2015. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Departmental Honors. / Discipline: Economics.

by Leung Yun-to, Ada. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 114-115). / Acknowledgment --- p.i / Abstract --- p.ii / Chapter 1. --- INTRODUCTION / Chapter 1.1 --- Review of gas-liquid chromatographic and other chromatographic techniques --- p.1 / Chapter 1.2 --- "Structures, actions and uses of the drugs under study" --- p.5 / Chapter 1.3 --- Research objectives --- p.10 / Chapter 2. --- INSTRUMENTATION AND THEORY / Chapter 2.1 --- Instrumentation for gas chromatography --- p.11 / Chapter 2.2 --- Basic principles in chromatography --- p.23 / Chapter 3. --- EXPERIMENTAL / Chapter 3.1 --- Instrumentation --- p.27 / Chapter 3.2 --- "The counter-check GC method for camphor, menthol and methyl salicylate" --- p.29 / Chapter 3.3 --- The counter-check HPLC method for thymol --- p.29 / Chapter 3.4 --- The counter-check HPLC method for phenol --- p.30 / Chapter 3.5 --- The counter-check HPLC method for benzoic acid --- p.31 / Chapter 3.6 --- The counter-check HPLC method for salicylic acid --- p.32 / Chapter 3.7 --- Reagents --- p.33 / Chapter 3.8 --- Sample preparation --- p.34 / Chapter 3.9 --- "Quantitative determination of benzoic acid, camphor, menthol, methyl salicylate, phenol, salicylic acid and thymol in various pharmaceutical preparations" --- p.35 / Chapter 4. --- RESULTS AND DISCUSSION / Chapter 4.1 --- Choice of column --- p.36 / Chapter 4.2 --- Optimization of chromatographic conditions --- p.44 / Chapter 4.3 --- Choice of solvent --- p.51 / Chapter 4.4 --- Calibration --- p.59 / Chapter 4.5 --- Reproducibility of the GC measurements --- p.95 / Chapter 4.6 --- Recovery test and precision studies --- p.96 / Chapter 4.7 --- Simultaneous determination of the drugs under study in various pharmaceutical preparations --- p.100 / Chapter 5. --- CONCLUSION --- p.113 / Chapter 6. --- REFERENCES --- p.114

Thesis. 1979. Ph.D.--Massachusetts Institute of Technology. Dept. of Economics. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND DEWEY. / Bibliography: leaves 176-179. / This thesis examines the effect that federal regulation of the product quality of new drugs (through safety and efficacy requirements) has had on the flow of new drugs onto the market place. The approach is to econometrically estimate these effects using disaggregated therapeutic class data from the 1970's. There are two primary estimations. First, the current effects of regulation on the production function relation between introductions and research expenditures are estimated. Second, the indirect effects of regulation on research effort are estimated in a research expenditures equation. These estimates are then combined to estimate the overall effect of regulation on introductions in the current era. In addition to the basic estimations described above, several important subsidiary issues are treated in the thesis. One is a discussion of the decline in new drug introductions of the 1962 era in terms of its individual therapeutic class components. This discussion gives strong support to the position that nonregulatory factors precipitated that decline in the rate of product introductions. Also, the project selection process of major pharmaceutical companies is examined in great detail. That discussion, and some econometric tests of hypotheses generated, clearly demonstrates that in order to predict how firms will respond to changes in environmental factors affecting profitability, one must first understand how firms collect, evaluate, and apply information concerning those factors. / Ph.D.

Foram desenvolvidas formulações de comprimidos do tipo matriz hidrofílica, contendo hidroxipropilmetil celulose, visando a liberação prolongada de rifampicina e isoniazida. Estudos de biodisponibilidade avaliaram a influência do pH do meio de dissolução da acidificação e alcalinização da matriz da modificação de porosidade e tortuosidade; das técnicas de preparação e da razão fármaco-agente formador da matriz. Os métodos de otimização e de estudos de correlação envolveram um plano experimental com quatro variáveis independentes e cinco níveis para cada uma. Para cada característica analisada foi construída uma equação, por regressão múltipla e a influência de cada variável independente foi analisada através de curvas isoresposta. / It was developed cellulose hidrophilic matrices, in order to provid a controlled release of isoniazid and rifampicin, anti-tuberculosis agents. The study of bioavailability brings to light the influence of the pH of the dissolution medium; of the acidification and alkalinization of the die; of the porosity and tortuosity of the production technic and of the drug-matrix raio. The optimization methods and correlational studies envolved an experimental plan with four independent variable and levels per variable. For each response variable, a multiple regression equation is established and the influence of each independent variable is identified by plotting combined and isoresponse curves.

Foram desenvolvidas formulações de comprimidos do tipo matriz hidrofílica, contendo hidroxipropilmetil celulose, visando a liberação prolongada de rifampicina e isoniazida. Estudos de biodisponibilidade avaliaram a influência do pH do meio de dissolução da acidificação e alcalinização da matriz da modificação de porosidade e tortuosidade; das técnicas de preparação e da razão fármaco-agente formador da matriz. Os métodos de otimização e de estudos de correlação envolveram um plano experimental com quatro variáveis independentes e cinco níveis para cada uma. Para cada característica analisada foi construída uma equação, por regressão múltipla e a influência de cada variável independente foi analisada através de curvas isoresposta. / It was developed cellulose hidrophilic matrices, in order to provid a controlled release of isoniazid and rifampicin, anti-tuberculosis agents. The study of bioavailability brings to light the influence of the pH of the dissolution medium; of the acidification and alkalinization of the die; of the porosity and tortuosity of the production technic and of the drug-matrix raio. The optimization methods and correlational studies envolved an experimental plan with four independent variable and levels per variable. For each response variable, a multiple regression equation is established and the influence of each independent variable is identified by plotting combined and isoresponse curves.

Doutoramento em Tecnologia Farmacêutica / PhD Degree - Pharmaceutical Technology / As ciclodextrinas são oligossacarídeos cíclicos com várias aplicações farmacêuticas. Apresentam uma cavidade central hidrofóbica, cuja estrutura permite formar complexos de inclusão estáveis com diversos fármacos. Neste trabalho, pretende-se associar as propriedades de complexação das ciclodextrinas à sua capacidade de promover a permeação de fármacos através da pele, utilizando como sistema transportador um adesivo transdérmico do tipo matricial em monocamada. O Naproxeno, sendo um fármaco pouco solúvel, constitui um bom modelo para a complexação com as ciclodextrinas. Foram desenvolvidos complexos binários de Naproxeno com as ciclodextrinas hidrossolúveis ß-ciclodextrina, hidroxipropil-ß- ciclodextrina e metil-ß-ciclodextrina, e complexos ternários utilizando as mesmas ciclodextrinas associadas com os polímeros hidrossolúveis polivinilpirrolidona e hidroxipropilmetilcelulose. Utilizando várias técnicas de análise, como estudos de solubilidade, a espectroscopia de ressonância magnética nuclear, a calorimetria de varrimento diferencial, a espectroscopia de infravermelho com transformadas de Fourier e a difracção de raios X, foi possível detectar e caracterizar os complexos de inclusão preparados, tanto em solução como no estado sólido. A avaliação das propriedades de dissolução do Naproxeno permitiu seleccionar os complexos com a ß-ciclodextrina e com a metil-ß-ciclodextrina, associados ou não com a hidroxipropilmetilcelulose, e preparados pelo método da coevaporação, como os melhores candidatos à preparação de formulações de libertação controlada para administração transdérmica. Os estudos de permeação do Naproxeno através da pele de porco, realizados com os adesivos transdérmicos desenvolvidos, demonstraram que o processo de permeação é influenciado pela matriz polimérica e que a sua cinética é linear com a raiz quadrada do tempo. Este trabalho permitiu obter um adesivo transdérmico contendo Naproxeno complexado com metil-ß-ciclodextrina-hidroxipropilmetilcelulose, promovendo a permeação do fármaco através da pele. / Cyclodextrins are ciclic oligosaccharides with several pharmaceutical applications. They present a central hidrophobic cavity, whose structure allows the formation of stable inclusion complexes with many drugs. The aim of this work is to combine the cyclodextrin complex formation properties with their capacity of enhancing the permeation of drugs across the skin, using as a delivery system a transdermic matricial monolayer patch. Naproxen, a poorly soluble drug, is a good model for preparing cyclodextrin complexes. Binary complexes of Naproxen and hydrophilic ß-cyclodextrin, hidroxipropil-ß-cyclodextrin and methyl-ß-cyclodextrin were prepared. Ternary complexes combining the same cyclodextrins, Naproxen and the water soluble polymers hydroxypropylmethylcellulose and polyvinylpyrrolidone were also prepared. The application of several techniques such as solubility assays, nuclear magnetic resonance spectroscopy, differential scanning calorimetry, Fourier transformation infrared spectroscopy and X-ray diffractometry, allowed the detection and characterization of the inclusion complexes both in solution and in the solid state. The dissolution properties of Naproxen were used to select the best candidates to the preparation of controlled release formulations for transdermic application. Based on those results the choice relied on Naproxen complexed with ß-cyclodextrin or methyl-ß-cyclodextrin, with or without the water soluble polymers, prepared by the coevaporation method. Naproxen permeation studies, performed in pig skin, gave evidence that the permeation process is influenced by the polymeric matrix and that the kinetics is linear with the square root of time. The present study allowed to obtain a transdermic patch, containing a Naproxen methyl-ß-cyclodextrin-hydroxypropylmethylcellulose complex that appropriately promotes Naproxen permeation through the skin.

Doutoramento em Química Farmacêutica / PhD Degree - Pharmaceutical Chemistry