Diabetes has become a nationwide epidemic affecting 18.2 million Americans, and the incidence is expected to increase 122% by the year 2025. The dyslipidemia associated with type 2 diabetes—low HDL-C; high TG; and small, dense LDL-C—contributes to the 2 to 4 times greater risk of individuals with diabetes to have a major cardiovascular event. Niacin, a B vitamin, and aerobic exercise have been shown separately to favorably alter the lipid profile. The present study examined a combination therapy of Niaspan®, an extended-release formulation of niacin, and 16 weeks of aerobic exercise in 23 individuals with type 2 diabetes. The dosage of Niaspan® began at 500 mg/day and increased 500 mg/day every 4 weeks up to a maximum dose of 2000 mg/day. Subjects were advised to gradually progress their frequency, intensity, and duration of aerobic exercise until they were expending at least 1500 kilocalories by week 8. Subjects were instructed to make no changes to their diet or diabetes medication regimen. Lipoproteins and subfractions and selected measures of physical fitness were examined before and after the 16 week intervention. Following the 16 week intervention period, there were significant changes (p<0.05) in HDL-C (+28%), TG (-19%), VLDL-C (-12%), and LDL-C (-9%). There were also significant changes in the larger, more buoyant subfractions HDL2 (+48%), VLDL2 (-15%) and LDL1 (-48%). Other subfractions that are smaller and more dense also changed favorably: HDL3 (+24%) and LDL4 (-15%). Although there was no significant weight loss in this population as a result of the intervention, there were significant changes in submaximal heart rate (124.9±17.6 vs. 116.7±16.3 bpm) and resting systolic (136.8±17.5 vs. 128.3±13.8 mmHg) and diastolic (80.3±12.5 vs. 73.2±9.8 mmHg) blood pressure, adaptations that occur with improvement in physical fitness. There were no changes in fasting plasma glucose or glycosylated hemoglobin, contradicting any deterioration in glucose control. Therefore, the combination of Niaspan® and aerobic exercise is effective at altering the lipid profile in individuals with type 2 diabetes. In addition, this intervention is safe in that it does not adversely affect glucose control. / School of Physical Education, Sport, and Exercise Science

Substituted tetrazines have been found to undergo facile inversed electron demand Diels-Alder reactions with “tunable” reaction rates. By varying the substituents on tetrazine, cycloaddition rate variations of over 200 fold have been achieved with the same dienophile. Coupled with the availability of different dienophiles, such as norbornene, the reaction rate difference can be over 14,000 folds. These substituted tetrazines can be very useful for selective labeling under different conditions. This finding paves the way to utilize tetrazine conjugation reactions for not only DNA but also stage labeling work. Carbon monoxide (CO) belongs to the gasotransmitter family of signalling molecules in the mammalian systems with importance on par with that of NO and H2S. Studies have shown that endogenous production of CO has anti-inflammatory, anti-proliferative, and anti-apoptotic effects in mammalian system. Besides of the conventional metal-based carbon monoxide releasing molecules (CORMs) to deliver CO for therapeutic purposes, organic CO prodrugs represent a new direction. Here we report the “click and release” approached to release CO. Unlike the metal-based CORMs, our system does not contain transition metal and liberates CO with controllable manner and possesses potential tunable releasing rate property under physiological conditions.

Tuberculosis (TB) is an infectious, deadly disease, caused by Mycobacterium tuberculosis (M.tb). In 2010, there were 8,8 million incident cases of TB globally. South Africa currently has the third highest TB incident cases worldwide. In an attempt to address the challenges facing TB chemotherapy, among which frequent dosing and long duration of therapy resulting in poor patient compliance, a novel poly(DL-lactic-co-glycolic) acid (PLGA) nanoparticulate drug delivery system (DDS) encapsulating anti-TB drugs was developed. It is hypothesised that this nanoparticulate DDS will address the challenges mentioned by enabling decreased dosing frequency, shortening duration of therapy and minimising adverse side effects. Therefore, favourable modification of pharmacodynamic (PD) and pharmacokinetic (PK) properties of the conventional anti-TB drugs was demonstrated. Furthermore, the nanoparticles will provide a platform for drug delivery to macrophages that serve as hosts for M.tb. The study design was based on determining specific physicochemical properties of the nanoparticulate DDS to elucidate the hypothesis. Spray-dried PLGA nanoparticles were prepared using the double emulsion solvent evaporation technique. In vivo analysis of macrophage uptake and possible immunological response in mice were evaluated. In vitro protein-binding assays of PLGA nanoparticles encapsulating anti-TB drugs isoniazid (INH) and rifampicin (RIF) were performed with subsequent in vivo tissue distribution assays to support protein-binding data generated. Finally, PK/PD analyses were conducted to evaluate the effect of nanoencapsulation on the anti-TB drugs. These involved in vitro assays to determine if sufficient drug was released from the nanoparticles to exhibit minimum inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC). Furthermore, in vivo drug distribution and drug release kinetics assays of encapsulated RIF, INH, pyrazinamide (PZA) and ethambutol (ETB) in a mouse model were performed. The results confirmed that the PLGA nanoparticles (<250 nm, low positive zeta potential) were taken up by macrophages in vivo with no significant immunological effect. Furthermore the nanoparticles were present in the brain, heart, kidneys, lungs, liver and spleen for up to 7 days following once-off oral dosing at 13.23± 0.11%, 16.81± 0.11%, 54.89± 0.95%, 15.61± 1.15%, 48.48± 2.28% and 5.73± 0.21%, respectively. This was further confirmed by drug analysis demonstrating the presence of INH, RIF and ETB at different time points up to 7 days in the lungs, kidneys, liver and spleen. However, PZA was not detected. Nanoencapsulated RIF and INH exhibited MICs and MBCs in vitro over 14 days and these drugs were also observed in plasma for up to 7 days post once-off oral dosing. ETB and PZA were observed up to 3 days. From the results generated, it can be concluded that the nanoparticles were taken up by macrophages without eliciting an immune response. This provides a platform for drug delivery to specific sites. Furthermore, the nanoparticulate DDS exhibited sustained drug release in vitro and in vivo over a number of days above the MIC for the drugs analysed. Sustained drug distribution was also observed. It can therefore be concluded that the hypothesised reduction in dose frequency and duration of therapy for this DDS is a possibility / Thesis (PhD (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

Tuberculosis (TB) is an infectious, deadly disease, caused by Mycobacterium tuberculosis (M.tb). In 2010, there were 8,8 million incident cases of TB globally. South Africa currently has the third highest TB incident cases worldwide. In an attempt to address the challenges facing TB chemotherapy, among which frequent dosing and long duration of therapy resulting in poor patient compliance, a novel poly(DL-lactic-co-glycolic) acid (PLGA) nanoparticulate drug delivery system (DDS) encapsulating anti-TB drugs was developed. It is hypothesised that this nanoparticulate DDS will address the challenges mentioned by enabling decreased dosing frequency, shortening duration of therapy and minimising adverse side effects. Therefore, favourable modification of pharmacodynamic (PD) and pharmacokinetic (PK) properties of the conventional anti-TB drugs was demonstrated. Furthermore, the nanoparticles will provide a platform for drug delivery to macrophages that serve as hosts for M.tb. The study design was based on determining specific physicochemical properties of the nanoparticulate DDS to elucidate the hypothesis. Spray-dried PLGA nanoparticles were prepared using the double emulsion solvent evaporation technique. In vivo analysis of macrophage uptake and possible immunological response in mice were evaluated. In vitro protein-binding assays of PLGA nanoparticles encapsulating anti-TB drugs isoniazid (INH) and rifampicin (RIF) were performed with subsequent in vivo tissue distribution assays to support protein-binding data generated. Finally, PK/PD analyses were conducted to evaluate the effect of nanoencapsulation on the anti-TB drugs. These involved in vitro assays to determine if sufficient drug was released from the nanoparticles to exhibit minimum inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC). Furthermore, in vivo drug distribution and drug release kinetics assays of encapsulated RIF, INH, pyrazinamide (PZA) and ethambutol (ETB) in a mouse model were performed. The results confirmed that the PLGA nanoparticles (<250 nm, low positive zeta potential) were taken up by macrophages in vivo with no significant immunological effect. Furthermore the nanoparticles were present in the brain, heart, kidneys, lungs, liver and spleen for up to 7 days following once-off oral dosing at 13.23± 0.11%, 16.81± 0.11%, 54.89± 0.95%, 15.61± 1.15%, 48.48± 2.28% and 5.73± 0.21%, respectively. This was further confirmed by drug analysis demonstrating the presence of INH, RIF and ETB at different time points up to 7 days in the lungs, kidneys, liver and spleen. However, PZA was not detected. Nanoencapsulated RIF and INH exhibited MICs and MBCs in vitro over 14 days and these drugs were also observed in plasma for up to 7 days post once-off oral dosing. ETB and PZA were observed up to 3 days. From the results generated, it can be concluded that the nanoparticles were taken up by macrophages without eliciting an immune response. This provides a platform for drug delivery to specific sites. Furthermore, the nanoparticulate DDS exhibited sustained drug release in vitro and in vivo over a number of days above the MIC for the drugs analysed. Sustained drug distribution was also observed. It can therefore be concluded that the hypothesised reduction in dose frequency and duration of therapy for this DDS is a possibility / Thesis (PhD (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

Controlled release formulations offer many advantages over conventional dosage forms. These include reduced plasma fluctuations and improved patient comp1i:nce. Complex controlled release formulations such as those with enteric release properties, often require additional steps in the production phase. The costs and economic impact associated with these complex controlled release dosage formulations often outweigh the immediate benefits. Thus the development of an economic method to produce controlled release particles is of great importance especially in third world countries. In controlled release formulations, the drug is generally dispersed throughout a polymer matrix. The rate of drug release is often determined by the viscosity or complexity of the polymer matrix through which the drug needs to diffuse in order to be released. With enteric release the polymer coating, insoluble in an acidic environment is often applied in the final phase of production. Chitosan is a versatile polymer of natural origin with many favourable characteristics. These include its safety, biocompatibility, and biodegradability. Simple methods can be applied and modified to produce controlled release particles form chitosan. The effect of modern controlled release polymers such as Aqoat AS-HF, Eudragit SlOO and Kollidon SR was investigated. Chitosan beads and chitosan-polymer beads, as well as chitosan granules and chitosan-polymer granules, were prepared and investigated as possible controlled release formulations. Ketoprofen was chosen as the model drug. Chitosan beads and chitosan-polymer beads were prepared by inotropic gelation in tripolyphosphate. Chitosan granules and chitosan-polymer matrix granules were prepared by binding chitosan with an acetic acid solution as a granulating system. The beads and granules appeared differed in appearance as well as in the results obtained from various experiments. Granules prepared in the study did not appear to be effective with regards to enteric and controlled release. Beads prepared form Kollidon SR appeared to be effective with regards to enteric and controlled release, with Kollidon 1% and 5% w/v chitosan beads achieving good drug loading of up to 73.13% and releasing less than 15 % of the total drug content in 0.1 M HCI after 60 minutes. Drug release continued steadily for up to 360 minutes in pH 7.2. It was concluded that Kollidon SR loaded chitosan beads nay be a viable controlled release dosage form with enteric release properties, and that future experiments, possibly with lower polymer concentrations, are worthwhile / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2006.

Controlled release systems aim at achieving a predictable and reproducible drug release profile over a desired time period. These controlled release formulations offer many advantages over conventional dosage forms. These advantages include: reduced dosing intervals, constant drug levels in the blood, increased patient compliance and decreased adverse effects. Complex controlled release formulations such as those with sustained release properties, often require additional steps during the production phase. The cost and economic impact associated with these complex controlled release dosage formulations often outweigh the short term benefits. Thus the development of an economic method to produce controlled release particles is of great importance especially in third world countries. In controlled release formulations the drug is often equally dispersed throughout a polymer matrix. In the presence of a thermodynamically compatible solvent, swelling occurs and the polymer releases its content to the surrounding medium. The rate of drug release can be controlled by interfering with the amount of swelling and rate of diffusion by manipulating the viscosity of the polymer matrix. Chitosan is an ideal candidate for controlled drug delivery through matrix release systems. It is a biodegradable polymer with absorption-enhancing properties. Cross-linking chitosan with different cross-linking agents allow the preparation of beads. Beads are frequently used in controlled release dosage forms as they are very flexible in dosage form development and show various advantages over single unit dosage forms. Because beads disperse freely in the gastrointestinal tract they maximize drug absorption, reduce fluctuation in peak plasma, and minimize potential side effects without lowering drug bio-availability. Chitosan beads and excipient containing chitosan beads were prepared and investigated as possible controlled release formulations. Pyrazinamide was chosen as the model drug. Chitosan beads and excipient containing chitosan beads were prepared by ionotropic gelation in tripolyphosphate. In this study chitosan/pyrazinamide beads containing pharmaceutical excipients (Ascorbic acid, Explotab and Ac-Di-Sol) were produced. The excipients were added individually and in combinations to the chitosadpyrazinamide dispersion and the beads were characterized on the basis of their morphology, solubility, fiability, drug loading capacity and swelling behaviour, as well as drug release (dissolution properties). The drug loading of the pyrazinarnide loaded chitosan beads, was 52.26 % 0.57%. It was noted that the inclusion of excipients in the beads resulted in an increase in drug loading with the combination of Ascorbic acid and Ac-Di-Sol giving the highest drug loading of 67.09 ± 0.22%. It was expected that the addition of the pharmaceutical excipients would lead to a sustained release of pyrazinamide. Dissolutions studies, however, revealed a burst release in both phosphate buffer solution (PBS) pH 5.60 and 7.40 over the first 15 minutes and the curve reached a plateau after 30 minutes. Thus, apparently the inclusion of the pharmaceutical excipients did not contribute to a sustained release of pyrazinamide over the tested period of six hours. In future studies the dissolution time can possibly be extended to a period of 24 hours. It might be possible for the remaining drug (approximately 40%) in the beads to be released over the extended period. Other polymers can also be investigated to control the release of pyrazinamide. Further studies are, however, necessary to investigate this possibility in the future. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

This document gives an overview of the proposed MSc study. The main goal of the study is to model the cases listed in the code benchmark study of the International Atomic Energy Agency CRP–6 fuel performance study (Verfondern & Lee, 2005). The platform that will be employed is the GETTER code (Keshaw & van der Merwe, 2006). GETTER was used at PBMR for the release calculations of metallic and some non–metallic long–lived fission products. GETTER calculates the transport of fission products from their point of fission to release from the fuel surface taking into account gas precursors and activation products. Results show that for certain experiments the codes correspond very well with the experimental data whilst in others there are orders of magnitude differences. It can be seen that very similar behaviour is observed in all codes. Improvements are needed in updating the strontium diffusion coefficient and in understanding, on a deeper level, the transport of silver in TRISO particles and how it deviates from simple diffusion models. / Thesis (M.Sc. Engineering Sciences (Nuclear Engineering))--North-West University, Potchefstroom Campus, 2012.

This dissertation examines two main research questions: Why do firms deviate from their predicted level of toxic emissions, and how do these differences relate to financial performance? The objective is threefold: (1) to understand deviation in corporate environmental performance by looking at both industry and firm level variables, (2) to see how this deviation relates to both profitability and fluctuations in financial performance, and (3) to see if, and how, corporate environmental legitimacy affects the relationship between corporate environmental deviation and corporate financial performance. To achieve this objective the construct “corporate environmental performance deviation” is developed. It is defined as the extent to which a firm’s environmental performance deviates from its predicted performance, and is used to capture within-firm strategic choices in environmental management. Predicted environmental performance is calculated based on certain firm characteristics such as size and industry. Actual environmental performance is calculated using a weighted score of air emissions obtained from the Toxic Release Inventory (TRI) database. The difference between these two values represents a corporation’s environmental performance deviation. Corporate environmental performance deviation focuses on strategic choices related to environmental management, while recognizing that environmental management is the result of both institutional pressures and within-firm strategic decisions. Aligned with this focus, variables 2 related to this strategic choice are used to explain deviation in environmental management, including an environmental integration capability, firm strategy, and industry munificence and dynamism. Associated with the internal and external organizational analysis, institutional theory and the resource-based view (RBV) are used to explore the tension between deviation to increase competitiveness versus isomorphism to attain legitimacy. The sample is composed of 311 U.S. firms who have reported their toxic air releases to the TRI from 1998-2007. The sample is broken down into two subsets, those that exceed (positive deviation) or fail to meet (negative deviation) predicted environmental performance. Results of a longitudinal analysis show that positive environmental deviation is related to a greater capacity to strategically integrate environmental issues into a firm’s existing business approach, less munificence and dynamism in the task environment, and reduced financial fluctuations. Negative environmental deviation is decreased through a demonstrated capacity to strategically integrate environmental issues into a firm’s existing strategic approach, and related to greater munificence and dynamism in the task environment, reduced profitability and increased financial fluctuations. Lastly, although there are no significant main effects for corporate environmental legitimacy, the paradoxical combination of negative deviation and environmental legitimacy can reduce the severity of the negative financial results to negative deviation, both in terms of profitability and financial fluctuations.

This document gives an overview of the proposed MSc study. The main goal of the study is to model the cases listed in the code benchmark study of the International Atomic Energy Agency CRP–6 fuel performance study (Verfondern & Lee, 2005). The platform that will be employed is the GETTER code (Keshaw & van der Merwe, 2006). GETTER was used at PBMR for the release calculations of metallic and some non–metallic long–lived fission products. GETTER calculates the transport of fission products from their point of fission to release from the fuel surface taking into account gas precursors and activation products. Results show that for certain experiments the codes correspond very well with the experimental data whilst in others there are orders of magnitude differences. It can be seen that very similar behaviour is observed in all codes. Improvements are needed in updating the strontium diffusion coefficient and in understanding, on a deeper level, the transport of silver in TRISO particles and how it deviates from simple diffusion models. / Thesis (M.Sc. Engineering Sciences (Nuclear Engineering))--North-West University, Potchefstroom Campus, 2012.

The molecular stress function model with convective constraint release (MSF with CCR) constitutive model [M.H. Wagner, P. Rubio, H. Bastian, The molecular stress function model for polydisperse polymer melts with dissipative convective constraint release, J. Rheol. 45 (2001) 1387] is capable of fitting all viscometric data for IUPAC LDPE, with only two adjustable parameters (with difference found only on reported ¿steady-state¿ elongational viscosities). The full MSF with CCR model is implemented in a backwards particle-tracking implementation, using an adaptive method for the computation of relative stretch that reduces simulation time many-fold, with insignificant loss of accuracy. The model is shown to give improved results over earlier versions of the MSF (without CCR) when compared to well-known experimental data from White and Kondo [J.L. White, A. Kondo, Flow patterns in polyethylene and polystyrene melts during extrusion through a die entry region: measurement and interpretation, J. Non-Newtonian Fluid Mech. 3 (1977) 41]; but still to under-predict contraction flow opening angles. The discrepancy is traced to the interaction between the rotational dissipative function and the large stretch levels caused by the contraction flow. A modified combination of dissipative functions in the constraint release mechanism is proposed, which aims to reduce this interaction to allow greater strain hardening in a mixed flow. The modified constraint release mechanism is shown to fit viscometric rheological data equally well, but to give opening angles in the complex contraction flow that are much closer to the experimental data from White and Kondo. It is shown (we believe for the first time) that a constitutive model demonstrates an accurate fit to all planar elongational, uniaxial elongational and shear viscometric data, with a simultaneous agreement with this well-known experimental opening angle data. The sensitivity of results to inaccuracies caused by representing the components of the deformation gradient tensor to finite precision is examined; results are found to be insensitive to even large reductions in the precision used for the representation of components. It is shown that two models that give identical response in elongational flow, and a very similar fit to available shear data, give significantly different results in flows containing a mix of deformation modes. The implication for constitutive models is that evaluation against mixed deformation mode flow data is desirable in addition to evaluation against viscometric measurements.