Low water solubility of drug compounds limits their dissolution in the aqueous body fluids. When formulated using conventional methods, those poorly water-soluble drugs often results in low and erratic bioavailability. The use of nanoparticle engineering technologies for the formulation of poorly water-soluble drugs is a valuable strategy to enhance dissolution rates and thus bioavailability. In Chapter 2, a nanoparticle engineering process, Evaporative Precipitation into Aqueous Solution (EPAS), was modified to provide improved control over the size of precipitated particles. The improved process, Advanced EPAS, was employed to prepare nanoparticles of the poorly water-soluble drug itraconazole (ITZ). The influence of processing parameters and formulation aspects on the size of suspended ITZ-particles was investigated. The process was shown to be robust such that the size distribution of dispersed nanoparticles was largely independent across the different parameters. In Chapter 3, aqueous nanoparticulate dispersions of the poorly soluble drug mefenamic acid (MFA) were developed and subsequently incorporated into controlled release formulations employing spray-drying. Release of MFA from spray-dried formulations was sustained and complete demonstrating the feasibility of using nanoparticulates for the preparation of controlled release systems. In Chapter 4, the nanoparticle engineering process, Rapid Freezing (RF), was utilized to produce nanostructured, amorphous aggregates of the poorly water soluble drug ketoprofen (RF-KET). The stability of RF-KET against recrystallization was improved through the deposition of a hydrophobic plasma-polymerized film. The coating presented an effective barrier against surface mobility and moisture uptake resulting in enhanced stability of RF-KET for up to six months at accelerated storage conditions as compared to three days for uncoated RF-KET. / text

No description available.

Thesis (Ph. D.)--Lehigh University, 1997. / Includes vita. Includes bibliographical references.

Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2008. / Christoph J. Fahrni, Committee Member ; Mostapha A. El-Sayed, Committee Member ; Christopher W. Jones, Committee Member ; Marcus Weck, Committee Chair ; E. Kent Barefield, Committee Member.

Membrane fusion plays a crucial role in many biological processes from virus infection to release of neurotransmitters (Hughson 1999). Membrane -bound surface glycoproteins are involved in the fusion process. The enveloped animal virus infection is initiated by interactions between the virus and the cell membrane through the surface glycoproteins called fusion glycoproteins (Eckert and Kim 2001). The fusion glycoproteins are responsible for both receptor binding and membrane fusion activity. The fusion proteins are characterized by a large ectodomain containing fusion peptides, a transmembrane (TM) domain, and a cytoplasimic domain. The viruses can enter cells either at neutral pH or at acidic pH. When exposed to appropriate conditions, the fusion protein undergoes conformational changes, which in turn drives the fusion process. The fusion glycoproteins can be classified as Class I and Class II fusion proteins (Lescar eta/. 2001 ). The Class I fusion proteins are synthesized as a precursor molecule, which then undergoes proteolytic cleavage to generate a mature molecule containing the hydrophobic fusion peptide at the N -terminal. The class II fusion glycoproteins are not synthesized as precursor molecules, and they have internal fusion peptides. The vesicular stomatitis virus (VSV) glycoprotein G is a class Ill fusion protein. It has a neutral internal fusion peptide and upon exposure to low pH, the protein undergoes reversible conformational change (Gaudin 2000, Yao eta/. 2003). A 62kDa soluble ectodomain of VSV G (Gs) has been generated by limited trypsin digestion. The SDS PAGE gel electrophoresis indicates that the trypsin has possibly cleaved near the transmembrane (TM) domain. Liposome binding experiment suggests that Gs can bind to liposomes in a pH dependent manner. Liposome fusion studied by RET assay suggests that the Gs can induce significant amount of hemifusion. However, it failed to induce any content mixing mainly due to considerable amount of membrane leakage activity. This indicates that the binding to the membrane through the TM domain is required for complete membrane fusion. Unlike TBE E soluble ectodomain, Gs can form dimers and trimers at neutral and fusion active pH. Light scattering experiment shows that the aggregation of Gs increases with a decrease in pH. The conformational change with changes in pH was evident from the trypsin sensitivity assay and CD spectroscopy. It was observed that Gs became resistant to trypsin digestion at low pH and a-helicity content of the molecule increased upon lowering the pH. However, the maximum amount of a-helicity was observed at pH 6. The removal of the TM domain also shifts the optimum fusion pH towards more acidic pH in comparison to VSV G. These results indicate that the TM domain is not required for the oligomerization of G protein, but some role has been reserved for the TM domain during membrane fusion. The CD spectroscopic data also indicated that the G protein undergoes structural rearrangement between pH 7.4-6, which could be responsible for the exposure of fusion peptide and subsequent target membrane binding. / Thesis / Master of Science (MSc)

Note:

The primary focus of this study was to compare the efficiency of six filter samplers in the collection of inhalable soluble platinum (Pt) salts at a South African base metal refinery. Inhalation remains the major route of occupational exposure to platinum groups metals (PGMs). South Africa would benefit from the study since it’s amongst the major countries where PGMs are produced and hence, monitoring of worker exposure with the most efficient sampler is of utmost importance. The IOM is currently being used in routine exposure monitoring although no studies have been carried out to compare its performance to that of the other samplers under the actual base metal refinery conditions. Method: The button, closed face cassette (CFC), Gesamtsstaubprobenhome (GSP), (Institute of Medicine) IOM, PAS-6 and seven hole (SH-sampler) samplers were randomly allocated to six different positions in presumably high exposure areas. The samplers were moved around in the subsequent sampling days and the process repeated 3 times. The average dust mass and Pt concentrations were used as a basis of sampler performance and comparisons from which sampler hierarchies were determined. Results: The average relative humidity ranged between 37% and 43% and the average dry bulb temperature of 22.4°C was measured. Comparison of the dust mass concentrations revealed no statistically significant differences amongst the six filter samplers tested. The SH-sampler and CFC however collected the highest and lowest dust mass and Pt concentrations respectively. Discussion: The SH-sampler was found to be a sampler with more reliability than the the IOM for the collection of dust mass and soluble Pt. The IOM collected 98% of the SH-sampler dust mass and Pt concentrations. This was in spite of the larger variations indicated by the highest relative standard deviations and confidence intervals shown by the IOM than the other samplers. The GSP sampler, however, showed better precision than all the other samplers in the collection of platinum. The seven 4 mm orifices of the SH-sampler sampler allow for uniform distribution of sampled particles onto the filter supporting its better precision than the IOM which has only one 4 mm opening. The worst performing sampler was the CFC sampler since it collected the lowest dust mass and Pt concentrations. The CFC and the PAS samplers have downward facing inlets that are affected by gravity especially in lower wind speeds which, therefore, influences their efficiency. The GSP sampler concentrations placed it as 4th and 3rd best in Pt and dust mass hierarchies respectively even though it showed better precision than SHS in the sampling of Pt. The button sampler did not perform as well as would have been expected considering that its many evenly spaced orifices and the stainless steel are meant to reduce sample losses. Conclusion: The sampler hierarchy according to dust mass concentrations was in the following order: SH-sampler, IOM, PAS, GSP, button and CFC. The hierarchy obtained from Pt concentrations gave the order as SH-sampler, IOM, GSP, button, PAS and CFC. Similar studies have to be undertaken in primary and secondary platinum workplaces to validate the study results. Such studies should compare better performing samplers (SHS, IOM, Button and GSP) as well as incorporate particle size determination and distribution in those areas. / MSc (Occupational Hygiene), North-West University, Potchefstroom Campus, 2014

The primary focus of this study was to compare the efficiency of six filter samplers in the collection of inhalable soluble platinum (Pt) salts at a South African base metal refinery. Inhalation remains the major route of occupational exposure to platinum groups metals (PGMs). South Africa would benefit from the study since it’s amongst the major countries where PGMs are produced and hence, monitoring of worker exposure with the most efficient sampler is of utmost importance. The IOM is currently being used in routine exposure monitoring although no studies have been carried out to compare its performance to that of the other samplers under the actual base metal refinery conditions. Method: The button, closed face cassette (CFC), Gesamtsstaubprobenhome (GSP), (Institute of Medicine) IOM, PAS-6 and seven hole (SH-sampler) samplers were randomly allocated to six different positions in presumably high exposure areas. The samplers were moved around in the subsequent sampling days and the process repeated 3 times. The average dust mass and Pt concentrations were used as a basis of sampler performance and comparisons from which sampler hierarchies were determined. Results: The average relative humidity ranged between 37% and 43% and the average dry bulb temperature of 22.4°C was measured. Comparison of the dust mass concentrations revealed no statistically significant differences amongst the six filter samplers tested. The SH-sampler and CFC however collected the highest and lowest dust mass and Pt concentrations respectively. Discussion: The SH-sampler was found to be a sampler with more reliability than the the IOM for the collection of dust mass and soluble Pt. The IOM collected 98% of the SH-sampler dust mass and Pt concentrations. This was in spite of the larger variations indicated by the highest relative standard deviations and confidence intervals shown by the IOM than the other samplers. The GSP sampler, however, showed better precision than all the other samplers in the collection of platinum. The seven 4 mm orifices of the SH-sampler sampler allow for uniform distribution of sampled particles onto the filter supporting its better precision than the IOM which has only one 4 mm opening. The worst performing sampler was the CFC sampler since it collected the lowest dust mass and Pt concentrations. The CFC and the PAS samplers have downward facing inlets that are affected by gravity especially in lower wind speeds which, therefore, influences their efficiency. The GSP sampler concentrations placed it as 4th and 3rd best in Pt and dust mass hierarchies respectively even though it showed better precision than SHS in the sampling of Pt. The button sampler did not perform as well as would have been expected considering that its many evenly spaced orifices and the stainless steel are meant to reduce sample losses. Conclusion: The sampler hierarchy according to dust mass concentrations was in the following order: SH-sampler, IOM, PAS, GSP, button and CFC. The hierarchy obtained from Pt concentrations gave the order as SH-sampler, IOM, GSP, button, PAS and CFC. Similar studies have to be undertaken in primary and secondary platinum workplaces to validate the study results. Such studies should compare better performing samplers (SHS, IOM, Button and GSP) as well as incorporate particle size determination and distribution in those areas. / MSc (Occupational Hygiene), North-West University, Potchefstroom Campus, 2014

No description available.

Background: Proteomic approaches identifying biomarkers have been applied to asthma to only a very limited extent. Methods: With an antibody array (RayBiotech, Norcross, GA, USA), the relative intensity and rank differences of 444 proteins were compared in 24 plasma samples obtained at age 3, 11 from children with and 12 without asthma diagnoses at ages 5 and 9. Protein candidates identified by antibody array were quantitated by ELISA in an enlarged sample. Proteins found to differentiate children with and without asthma were also examined for association with known Year 1 asthma risk factors, eczema, and wheeze. Results: In the antibody array, four proteins had rank differences between asthma and non-asthma groups (FDR < 0.1). By ELISA, mean log (+/- s.e.m.) erythropoietin (EPO) level (IU/l) was lower (0.750 +/- 0.048 vs. 0.898 +/- 0.035; p = 0.006) and mean (+/- s.e.m.) soluble GP130 (sGP130) level (ng/ml) was higher in the asthma vs. the non-asthma group (302 +/- 13 vs. 270 +/- 8; p = 0.041). The other 2 array proteins (galactin-3 and eotaxin-3) did not differ by ELISA by asthma. EPO related to the asthma risk factor, first year eczema, whereas sGP130 related to first year wheeze. Conclusions: Through two independent assessments, age 3 plasma levels of EPO and sGP130 were found related to childhood asthma.