http://hdl.handle.net/10150/129652 Sun, 09 Jul 2017 18:03:57 GMT 2017-07-09T18:03:57Z http://hdl.handle.net/10150/624661 Title: The Development of Beat Patterns from 1672 -1763: An Historical Perspective Author: Long, Wallace H., Jr. Abstract: A common misconception in our understanding of the history of conducting stems from a failure to identify properly the origin of beat patterns. Berlioz's L'Art du chef d'orchestra, written in 1844, has long been accepted as the first major text to codify both the principles of conducting and the beat-patterns conductors have employed to facilitate communication with performers.The beat-patterns illustrated in L'Art du chef d'orchestre had actually been in existence for well over a century before Berlioz wrote about them. The present study will document the existence of beat patterns prior to 1844 and examine their influence on performance practice. Sat, 01 Jan 1983 00:00:00 GMT http://hdl.handle.net/10150/624661 1983-01-01T00:00:00Z http://hdl.handle.net/10150/624660 Title: Le Tombeau de Couperin Author: Nichols, Ralph Tue, 01 Jan 1980 00:00:00 GMT http://hdl.handle.net/10150/624660 1980-01-01T00:00:00Z http://hdl.handle.net/10150/624590 Title: Molecular and Chemical Modulation of NRF2 for Disease Intervention Author: Harder, Bryan Abstract: Cells are frequently exposed to endogenous and environmental stressors that pose a threat to homeostatic cellular conditions. In response to such stress, the cell activates an adaptive antioxidant response, which is regulated by the transcription factor NRF2 to mitigate the harmful effects of electrophilic or oxidative species. Pharmacological activation of NRF2 has shown to be effective for preventing the initiation and promotion of cancer, neurodegenerative diseases, and other chronic illnesses, leading to the search for more specific molecules that activate this pathway. Intriguingly, because it is a pro-survival factor, NRF2 is frequently found to be deregulated in many cancer types that are resistant to chemotherapy, calling for the use of NRF2 inhibitors as an adjuvant therapy to enhance the effects of primary chemotherapeutic regimens. In this dissertation, detailed molecular studies have identified a new mechanism by which NRF2 can be aberrantly up-regulated in Type 1 endometrial carcinoma. Additionally, key mechanistic approaches were undertaken to understand the biological consequence of the first NRF2 inhibitor, brusatol. Furthermore, strategic approaches to identify novel chemical modulators of the NRF2 pathway were used, using natural products as a primary source. Assessment of the mechanism of action of biological activity for chemical modulators of the NRF2 pathway was of extreme interest, and rational approaches for the use of these compounds for disease intervention based on disease context will be discussed. Strat-MTM is a synthetic model for transdermal diffusion testing made by EMD Millipore and was marketed as a new skin mimetic membrane. It has been reported to be predictive of diffusion in human skin. Independent researchers had evaluated this membrane and compared it with animal and human skin and other polymeric membranes. Yet, there are not a published research to correlate the animal skin and Strat-MTM based on the amount of drug retained after topical application, which is one of the critical criteria for dermal drug delivery system. In this research, five compounds, with various physiochemical properties, were selected to perform this correlation. Resatorvid, Methyl Para aminobenzoate (M-PABA), Diclofenac sodium, Salicylic acid and hydrocortisone, each one was dissolved in phosphate buffer saline (pH 7.4) in concentrations of 60 ug/ml for resatorvid and 100-120 ug/ ml for others. All experiments were uniform in the setting and made in triplicate. As a conclusion from the results, the number of tested compounds were shorted to reflect the correlation in flux or permeability coefficient between murine skin and Strat-MTM membrane. With exception of M-PABA, there is a trend of correlation with the percentage of drug retained in dermis layers; however, the number of compounds still low to reflect a real correlation. Sun, 01 Jan 2017 00:00:00 GMT http://hdl.handle.net/10150/624590 2017-01-01T00:00:00Z http://hdl.handle.net/10150/624589 Title: Preformulation and Topical Penetration Studies Author: Aodah, Alhassan Abstract: Chapter I: preformulation studies on piperlongumine Piperlongumine is a natural alkaloid extracted from piper plant which has been used traditionally for the treatment of certain diseases. This compound shows interesting in-vitro pharmacological activity such as selective anticancer activity and higher cytotoxicity than methotrexate, cyclophosphamide and adriamycin on breast, colon, and osteosarcoma cancers, respectively. However, the physicochemical properties of this compound have not been well characterized. In this research, preformulation studies for piperlongumine have been performed to determine factors which influence solubility and stability which, in turn, can be used to assist future formulation development. The solubility of piperlongumine in water was found to be approximately 26 μg/ml. Using 10% polysorbate 80 as a surfactant resulted in a 27 fold increase in solubility. Cosolvents and cyclodextrins afforded concentrations of 1 mg/ml and higher. The pH degradation rate profile for piperlongumine at various temperatures shows significant instability of the drug at pH values 7 and 3, and maximum stability around pH 4. It was estimated that it would take approximately 17 weeks for piperlongumine to degrade by 10% at 25°C, pH 4. Additionally, piperlongumine showed marked photo-degradation upon exposure to an ultraviolet light source, especially in aqueous media. Chapter II: preformulation and evaluation of resatorvid topical delivery Resatorvid is a small molecule shows interesting anti- inflammatory biological activity. The clinical trial was conducted for sepsis-induced cardiovascular and respiratory failure, but it was terminated due to low efficacy. Further researches show a different biological activity of resatorvid such as its activity against UV-induced skin cancer. The goal of this study is to determine some important physiochemical properties of resatorvid, as well as intrinsic penetration criteria through the murine skin, either ex-vivo or in-vivo. Intrinsic water solubility of resatorvid was found to be 95.32± 1.75 ug/ml and could be duplicated by using 10 % ethanol as cosolvent. The pH solubility profile shows the acidic pka value of resatorvid is around 8-8.1. Photo-stability results indicate more stability in non-aqueous more than aqueous medium. Resatorvid pH degradation rate profiles indicate the maximum stability between pH3 -5 and maximum instability at pH 8 and 9 at all experimental temperatures over 26 days. T90 at 25 °C was 648 days in pH 3 versus 11 days in pH 9. Ex-vivo penetration evaluation for resatorvid through hairless murine skin was evaluated using acetone and phosphate buffer formulations. The flux values were 0.82 and 0.36 for acetone and phosphate buffer formulation respectively. The percent of drug retention in the dermis layer of skin were also evaluated and found to be 37.99% for the acetone formulation and 21.13 % for phosphate buffer formulation. The in-vivo penetration evaluation study was performed by topically applying of resatorvid in acetone solution. Skin biopsy from the site of application was analyzed one, three, eight and 24 hours post-application. The analysis was performed by tape stripping of the stratum corneum of the skin segment. It was found that percent of resatorvid at the dermis layers 5.92, 1.47, 0.45 and 0.23 % for 1, 3, 8 and 24 hours post-application respectively. The percent of resatorvid retention in dermis layer from the in-vivo study are not in compliance with the result of the ex-vivo study, which could refer to possible enzymatic degradation of resatorvid in the live animal skins. Chapter III: correlation of drug penetration between Strat-MTM membranes and murine skin for various drugs. Strat-MTM is a synthetic model for transdermal diffusion testing made by EMD Millipore and was marketed as a new skin mimetic membrane. It has been reported to be predictive of diffusion in human skin. Independent researchers had evaluated this membrane and compared it with animal and human skin and other polymeric membranes. Yet, there are not a published research to correlate the animal skin and Strat-MTM based on the amount of drug retained after topical application, which is one of the critical criteria for dermal drug delivery system. In this research, five compounds, with various physiochemical properties, were selected to perform this correlation. Resatorvid, Methyl Para aminobenzoate (M-PABA), Diclofenac sodium, Salicylic acid and hydrocortisone, each one was dissolved in phosphate buffer saline (pH 7.4) in concentrations of 60 ug/ml for resatorvid and 100-120 ug/ ml for others. All experiments were uniform in the setting and made in triplicate. As a conclusion from the results, the number of tested compounds were shorted to reflect the correlation in flux or permeability coefficient between murine skin and Strat-MTM membrane. With exception of M-PABA, there is a trend of correlation with the percentage of drug retained in dermis layers; however, the number of compounds still low to reflect a real correlation. Sun, 01 Jan 2017 00:00:00 GMT http://hdl.handle.net/10150/624589 2017-01-01T00:00:00Z