There is extensive research focused on identifying predictors of autism, including biomarkers such as genes and neurophysiology. Because of inconsistent data, I explored these biomarkers as predictors of variability in behavioral outcomes (i.e., internalizing and externalizing symptoms), rather than indicators of the disorder per se. In a sample of children (ages 8-16) diagnosed with High Functioning Autism (HFA) and an age- and IQ- matched typically developing comparison group, individual differences in behavioral outcomes were assessed in relation to common genetic polymorphisms, 5-HTTLPR and DRD4, and neurophysiological (ERN) and behavioral (rate of self-correction) measures of response monitoring. Although the diagnostic groups did not differ on allele frequency for 5-HTTLPR, carriers of the L variant displayed attenuated ERN amplitudes at frontal-central sites, lower rates of self-correction following errors, and higher levels of parent-reported Somatization and Hyperactivity. With respect to DRD4, an overrepresentation of the 7-repeat allele was found in the HFA sample. Regardless of diagnostic group, 7-repeat allele carriers were rated as having more attention problems. These results suggest that genetics and neural correlates of response monitoring may explain interindividual variations in social emotional functioning of both HFA and typically developing children alike. However, contrary to hypothesis, response monitoring did not mediate the association between 5-HTTLPR or DRD4 and outcome measures. Future directions of this research may look at how genes and measures of response monitoring affect etiology, course, and treatment of autism and other related disorders.

Asthma is a significant lung disease involving chronic inflammation and remodeling of the airways, resulting in reduced quality of life for those who suffer from the condition. Current therapeutic guidelines suggest the use of inhaled corticosteroids for long-term anti-inflammatory relief to manage moderate to severe chronic asthma; however, inhaled corticosteroids fail to provide prophylactic or reversal treatment of damaged airways incurred by chronic asthma as well as exhibiting adverse side effects (skeletal complications, diabetes, and weight gain).Therefore, there is a need for a new type of drug therapy to address these gaps in the treatment of chronic asthma. There is growing interest aimed towards the inhibition of the Janus Kinase and Signal Transducer and Activator of Transcription (JAK-STAT) pathway for the treatment of asthma. Despite the promising opportunity to investigate this new pathway towards this clinical application, no published work is available using an established and characterized JAK 1/3 inhibitor for the treatment of chronic asthma delivered via inhalation. This work investigated tofacitinib citrate, a selective JAK 3 inhibitor, and its potential to be delivered locally to the lungs for the treatment of chronic asthma. Several preformulation studies were conducted to determine the basic physical and chemical properties of the compound and its free base, tofacitinib, for proper inhalational formulation development. The drug was delivered to BALB/c mice challenged with house dust mite (HDM) allergen via nebulization utilizing a nose-only chamber. After a three week dosing schedule, mice treated with tofacitinib citrate exhibited an increase in monocyte cell numbers with a simultaneous decrease in eosinophil cell count, gathered from BAL fluid. Further, the experimental groups treated with tofacitinib citrate had a decrease in total protein concentrations in comparison to the experimental groups that were only challenged with HDM or were both exposed to HDM and vehicle. These findings demonstrated that the proper formulation was developed for nebulized delivery of tofacitinib citrate, and that the compound was capable of reducing total protein concentrations and eosinophil cell recruitment, both recognized as biomarkers for an asthmatic response. Although significant work is still needed to be done, these data hold promise for the potential of a locally delivered JAK 3 inhibitor as a treatment for chronic asthma. Further, the solubility of tofacitinib citrate and five other pharmaceutical salts were determined in HFA 134a, HFA 227, and DFP with varying cosolvent content (0-20% v/v ethanol). The experimental solubilities of the free acid and base compounds were larger than the solubilities of their respective salts in all three systems for tofacitinib, albuterol, and salicylic acid. Warfarin, phenytoin, and ciprofloxacin had similar solubilities with their respective salt forms. Solubilities also increased with increasing cosolvent concentration for all compounds investigated. The model propellant, DFP, provided a slightly stronger correlation of solubility values with HFA 134a in comparison to HFA 227. The observed solubility values were also compared to calculated values obtained from the ideal solubility model, where it was determined that the observed solubility was indeed also dependent on its surrounding solvent interactions and not solely on its ideal solubility (melting point). While some physical changes were observed for the pharmaceutical salts in HFA 134a and 227, more quantitative studies are needed for a larger database of compounds to better understand the factors that contribute to the solubility of pharmaceutical salts (and their correlation to DFP), in HFA-based systems. This information could potentially contribute to a predictive model, saving time and money during the process of pMDI formulation development.

The reformulation of pressurized metered dose inhalers (MDIs) with hydrofluoroalkanes (HFAs) from chlorofluorocarbons (CFCs) has given rise to many solubility challenges. Compounds and excipients previously used in CFCs were observed to have significantly different solubility values in HFA-134a. In this investigation, the solubility values of solid organic solutes were determined in pure HFA-134a and HFA-134a with cosolvent (0 - 20% w/w ethanol). The solubilities of solid solutes in HFA-134a were also compared with those in 2H,3H-decafluoropentane (DFP) in order to assess the suitability of DFP as a liquid model propellant. The experimental set of solutes display diverse physico-chemical properties and yielded solubility values that ranged over four orders of magnitude. The experimental solubilities were compared to calculated values obtained from ideal solubility and regular solution theory models. While the theoretical models did not offer absolute solubility estimations, a clear correlation with the ideal solubility (melting point) was noted. Further consideration utilizing multiple linear regression models afforded correlations based on molecular properties. Regression models, containing melting point and logP (or molar volume) resulted in promising correlations in both pure HFA-134a and HFA-134a/cosolvent systems where the average absolute errors ranged from 0.49 to 0.82 log units, (average factor errors of 3.09 and 6.61, respectively). In general, a linear relationship was observed between log mole fraction solubility in HFA-134a and fraction ethanol. The effect on solubilization ranged from 1.3 to 99.4 times when 20% w/w ethanol was introduced, relative to pure HFA-134a. DFP appears to be a promising liquid model for pure HFA-134a for pre-formulation calculations. A two parameter equation were found to be significant in pure HFA-134a where the average absolute error (AAE) value was 0.61 log units (average factor errors of 4.07).

There are a number of evidenced-based practices which aim to improve the social skills of children with high functioning autism (HFA). An emerging field of study is to develop social skills interventions that incorporate restricted and repetitive interests to increase social skills. Their results are promising and suggest improved social skills in students with HFA. The current study has aimed to incorporate a common interest among elementary age children with HFA in social skill instruction within a structured setting. A multiple baseline across behaviors single subject design was used to collect data on the accuracy with which two young males applied social skills within the structured “club” setting. Data were collected by determining whether the students had an opportunity to use the social skill, and whether they used the skill correctly. While the results do not suggest a functional relationships between the participants’ social skill accuracy and the intervention, the data show a positive trend which indicates an overall increase in their social skill accuracy.

Inhaled corticosteroids (ICS) are used to address inflammatory illnesses including asthma and COPD, with delivery commonly achieved using pressurised metered dose inhalers (pMDI). Hydrofluoroalkanes (HFAs) have been introduced as an alternative propellant to chlorofluorocarbons (CFCs) to reduce their environmental impact. However, the thermodynamic properties of HFAs are poorly understood and are different to those of CFCs. It is essential, therefore, to characterise the drugs and excipients used in HFA inhalers in order to obtain a comprehensive understanding of the device performance and the therapeutic efficacy. This work has developed different analytical methods to study the complexation between ICS and CD which are added to enhance the solubility of inhaled drugs in pMDI propellant systems providing rational control of suspension vs. solution formulations and hence their dose uniformity and stability. The Nuclear Magnetic Resonance (NMR) method developed has shown weaker complexation between budesonide and the derivatised CDs DIMEB and TRIMEB in organic solvents compared to D2O with the strength of the complex formed being ranked as D2O > MeOD > CDCl3 > CD3CN. The derivatisation of the CD also shows a marked difference in complexation with budesonide with the strength of the association being ranked as DIMEB > βCD > TRIMEB. Studies of various ICS compounds with TRIMEB in the fluorinated propellant HPFP showed the association to be greatest in budesonide, followed by beclomethasone dipropionate, momestasone furoate and fluticasone propionate. Surface-enhanced Raman scattering (SERS) has been used for the detection of corticosteroids in water using thiol functionalised βCD as a complementary study to NMR. This has been utilised to evaluate the host-guest complexes formed and provides further insight into the complexation of the compounds by their inclusion into the CD cavity. The structural data obtained using the NMR and SERS approaches developed have provided a fundamental insight into the physical chemistry of these interactions at a molecular level.

A fundamental characterization of hexafluoroalcohol substituted polynorbornene (HFAPNB) was completed to improve the final photoresist formulation using these materials. In this work, it was found that the dissolution behavior of these materials was controlled by the ability of polymer chains to form hydrogen bonds. This ability to form interchain hydrogen bonds was affected by stereochemical changes in the polynorbornene backbone as molecular weights increase. These observed changes in backbone polynorbornene stereochemistry were accurately modeled using the "helix-kink" theory, first described by Ahmed and Ludovice. It was found that several material properties altered the interchain hydrogen bonding within these materials, such as the polydispersity, polymerization catalyst, and the polymer film thickness. However, none of these material properties altered the unusual dissolution behavior observed in these materials. To improve the potential formulation of these materials, the interactions between HFAPNB and resist additives were studied. For all tested photoacid generators, it was found that some interchain hydrogen bonding occurred between resist additive molecules and HFA side groups, which retarded the dissolution rate in the formulated material. In particular, one can create a simple resist using unprotected HFAPNB polymer with an iodonium photoacid generator. Finally, a series of norbornene oligomers were evaluated as potential dissolution inhibitors for HFAPNB. It was found that the dissolution rate of HFAPNB can be completely inhibited with dissolution inhibitors at a loading of 15%.

This research explored in-vitro and in-vivo performance of three salbutamol metered dose inhalers (MDIs): Ventolin Evohaler (Evo), Airomir (Airo) and Salamol. In the in-vitro studies, critical quality attributes of the MDI using an Andersen cascade impactor (ACI) were examined and included measurement of fine particle dose (FPD) and total delivered dose (TDD). Bioequivalence studies were conducted in humans using the urinary pharmacokinetic method. Post-inhalation urinary excretion of salbutamol in the first 0.5 hour (lung deposition, USAL0.5) and over 24 hours (total systemic bioavailability, USAL24) were compared to determine the bioequivalence of the MDIs. The spacers recommended for use with these inhalers were also studied, and charcoal block studies were performed to assess the extent of USAL0.5. The three MDIs had FPD (μg) of 78, 91 and 89, respectively; the latter pair was equivalent. Their USAL0.5 (6, 7 & 7 μg) was however not bioequivalent. These MDIs delivered equivalent dose (177, 174 & 180 μg) which reflected on their USAL24 (101, 84 & 97 μg). Nevertheless, USAL24 was inequivalent between Evo and Airo. The FPD of Evo with Volumatic (VOL), AeroChamber Plus (AERO) and Able spacer was 78, 68 and 74 μg, respectively. The AERO treatment method was not equivalent to the MDI while VOL and Able were equivalent between them. Spacer USAL0.5 (16, 15 & 14 μg) was not bioequivalent to the MDI but to each other. The spacer in-vitro TDD (95, 85 & 92 μg) was inequivalent to the MDI treatment method. In contrast, their USAL24 was bioequivalent (97, 85 & 90 μg). The FPD of Airomir with AERO (95 μg) was in-vitro equivalent while USAL0.5 (15 μg) of this treatment method was bio-inequivalent to the MDI alone. On the contrary, the TDD (110 μg) and USAL24 (84 μg) of AERO were respectively in-vitro inequivalent and bioequivalent to the MDI alone. The FPD (μg) of Salamol MDI alone and with VOL (84) and AERO (86) as well as between the spacers was equivalent. However, the USAL0.5 of the MDI was not bioequivalent to spacers (20 and 18 μg) despite being equivalent between the spacers. In contrast, the respective TDD (103 and 95 μg) of spacer treatment methods were in-vitro inequivalent to the MDI alone albeit having bioequivalent USAL24 (86 and 87 μg). The variations in the in-vitro performance of the three MDIs are most likely due to differences in their formulations and designs. As the performance metrics of the MDI influence lung deposition, substituting one MDI with another can have clinical implications. Although the spacers reduced in-vitro TDD of the MDI to about half, their use increased lung deposition by over two folds, the magnitude of which varied with the MDI and spacer type. Despite significant decrease in dose delivery, the total systemic bioavailability with the spacers was similar to that with the MDI alone. This systemic bioequivalence is more likely due to greater USAL0.5 with the spacers. The results of the charcoal block studies reinforced this outcome. The present study is unique as it used a clinically relevant salbutamol MDI dose (two puffs), assessed results for equivalence and analysed ACI deposition data further as stage groups. The deposition on adjacent ACI stages were grouped together as coarse, fine and extra-fine particle masses to identify their more likely deposition sites in the human respiratory tract. Moreover, this thesis describes highly sensitive and novel HPLC and SPE methods, developed and validated to quantify salbutamol in urinary and aqueous matrices. As the clinical effects of MDIs are related to their lung deposition, the current work emphasizes the importance of spacer use. Nevertheless, differences in dose delivery between spacers may have clinical consequences. Hence, only the specific spacer recommended for use with the MDI should be used. / World Federation, Stanmore, London and Sadaat Welfare Foundation, Bradford, West Yorkshire

This thesis is based around examination of three mainstream inhaled drugs Formoterol, Budesonide and Beclomethasone for treatment of asthma and COPD. The areas investigated are these which have been raised in reports and studies, where there are concern, for drug use and assessment of their use. In reporting this work the literature study sets out a brief summary of the background and anatomy and physiology of the respiratory system and then discuses the mechanism of drug deposition in the lung, as well as the methods of studying deposition and pulmonary delivery devices. This section includes the basis of asthma and COPD and its treatment. In addition, a short section is presented on the role of the pharmacist in improving asthma and COPD patient's care. Therefore the thesis is divided into 3 parts based around formoterol, budesonide and beclomethasone. In the first case the research determines the in-vitro performance of formoterol and budesonide in combination therapy. In the initial stage a new rapid, robust and sensitive HPLC method was developed and validated for the simultaneous assay of formoterol and the two epimers of budesonide which are pharmacologically active. In the second section, the purpose was to evaluate the aerodynamic characteristics for a combination of formoterol and the two epimers of budesonide at inhalation flow rates of 28.3 and 60 L/min. The aerodynamic characteristics of the emitted dose were measured by an Anderson cascade impactor (ACI) and the next generation cascade impactor (NGI). In all aerodynamic characterisations, the differences between flow rates 28.3 and 60 were statistically significant in formoterol, budesonide R and budesonide S, while the differences between ACI and NGI at 60 were not statistically significant. Spacers are commonly used especially for paediatric and elderly patients. However, there is considerable discussion about their use and operation. In addition, the introduction of the HFAs propellants has led to many changes in the drug formulation characteristics. The purpose of the last section is to examine t h e performance of different types of spacers with different beclomethasone pMDIs. Also, it was to examine the hypothesis of whether the result of a specific spacer with a given drug/ brand name can be extrapolated to other pMDIs or brand names for the same drug. The results show that there are different effects on aerodynamic characterisation and there are significant differences in the amount of drug available for inhalation when different spacers are used as inhalation aids. Thus, the study shows that the result from experiments with a combination of a spacer and a device cannot be extrapolated to other combination.

Although disaster risk reduction is still not considered a priority by many countries and organisations, there is significant progress made towards the reduction of disaster risk. The experience of the International Decade for Natural Disaster Reduction (IDNDR, 1990–1999) prompted a major conceptual shift from disaster response to disaster reduction underscoring the crucial role of human action (UNISDR, 2001:03). This circumstance led to the adoption of an International Strategy for Disaster Risk Reduction (ISDR) in 1999 by the participants of the IDNDR Programme Forum. The adoption gave emphasis to the importance of a global strategy that encourages and facilitates concerted action to reduce risk and vulnerability to natural and related technological and environmental hazards. This research then focuses on the disaster risk reduction phenomenon and major or international initiatives and forums aimed at improving or raising the disaster risk reduction profile. It also focuses on disaster risk management in the South African context. In recent years, disaster risk reduction has grown in importance on the international agenda. This followed the prevalence of natural hazards such as floods, drought, earthquakes, tsunamis, as well as epidemics, which have had an increasing impact on humans, due to population growth, urbanization, rising poverty and the onset of global environmental changes. Aspects of environmental change include climate change, land degradation and deforestation. Practitioners and researchers widely acknowledge that poor planning, poverty and a range of other underlying factors create conditions of vulnerability that result in insufficient capacity or measures to reduce hazards‘ potentially negative consequences (IISD/UN/ISDR, 2007:01). It is in this light that in 2005 many governments around the world committed themselves to take action to reduce disaster risk, and thereby adopted a guiding document to reduce vulnerabilities to natural hazards, called the Hyogo Framework for Action (HFA). The HFA was adopted in January 2005 at the World Conference on Disaster Reduction, in Kobe Hyogo, Japan by 168 States. The aim of the HFA is to assist the efforts of nations and communities to become more resilient to, and cope better, with the hazards that threaten their development gains with the overriding goal of achieving a substantial reduction in global disaster risk. It also emphasizes that disaster risk reduction is a central issue for development policies, in addition to being of interest to various science, humanitarian and environmental fields. To help attain the expected outcome, the HFA identified five specific priorities for action (PFAs) which are: (i) making disaster risk reduction a priority; (ii) improving risk information and early warning; (iii) building a culture of safety and resilience; (iv) reducing the risks in key sectors; and (v) strengthening preparedness for response. The Global Network of Civil Society Organisation for Disaster Risk Reduction (GNDR) which was launched in 2007 in Geneva, is a major international network of civil society organisations working to influence and implement disaster risk reduction policies and practice around the world. The major programme of the global network is to collect perspective for the local level as to how the HFA is progressing. The Views from the Frontline (VFL) is the first independent assessment project undertaken towards the implementation of the HFA at the local level and is led by the Global Network. The aim of this project is to measure the gap between policy formulation at international level with the realities of policy execution at local level and to deepen the communication and coordination between different stakeholders on disaster risk reduction by involving government organisation and communities at the local level. The VFL perspective is that nationally formulated policies are not generating widespread systematic changes in local practices. There is a concern that the current approach is top–down and engages minimally with affected communities and fails to address their needs and capacities (GNDR, 2008:01). The main objective of this research was to provide an overview of progress made in the implementation of the HFA at local level particularly in the Kabokweni Location. The approach adopted in this study is called 'the Views from the Frontline', and explores the extent of the actual progress made toward the implementation and impact of the HFA priorities at local level, namely the Kabokweni community in the Mbombela Local Municipality (MLM) situated in the Mpumalanga Province of South Africa. / Thesis (M. Development and management)--North-West University, Potchefstroom Campus, 2011.

Although disaster risk reduction is still not considered a priority by many countries and organisations, there is significant progress made towards the reduction of disaster risk. The experience of the International Decade for Natural Disaster Reduction (IDNDR, 1990–1999) prompted a major conceptual shift from disaster response to disaster reduction underscoring the crucial role of human action (UNISDR, 2001:03). This circumstance led to the adoption of an International Strategy for Disaster Risk Reduction (ISDR) in 1999 by the participants of the IDNDR Programme Forum. The adoption gave emphasis to the importance of a global strategy that encourages and facilitates concerted action to reduce risk and vulnerability to natural and related technological and environmental hazards. This research then focuses on the disaster risk reduction phenomenon and major or international initiatives and forums aimed at improving or raising the disaster risk reduction profile. It also focuses on disaster risk management in the South African context. In recent years, disaster risk reduction has grown in importance on the international agenda. This followed the prevalence of natural hazards such as floods, drought, earthquakes, tsunamis, as well as epidemics, which have had an increasing impact on humans, due to population growth, urbanization, rising poverty and the onset of global environmental changes. Aspects of environmental change include climate change, land degradation and deforestation. Practitioners and researchers widely acknowledge that poor planning, poverty and a range of other underlying factors create conditions of vulnerability that result in insufficient capacity or measures to reduce hazards‘ potentially negative consequences (IISD/UN/ISDR, 2007:01). It is in this light that in 2005 many governments around the world committed themselves to take action to reduce disaster risk, and thereby adopted a guiding document to reduce vulnerabilities to natural hazards, called the Hyogo Framework for Action (HFA). The HFA was adopted in January 2005 at the World Conference on Disaster Reduction, in Kobe Hyogo, Japan by 168 States. The aim of the HFA is to assist the efforts of nations and communities to become more resilient to, and cope better, with the hazards that threaten their development gains with the overriding goal of achieving a substantial reduction in global disaster risk. It also emphasizes that disaster risk reduction is a central issue for development policies, in addition to being of interest to various science, humanitarian and environmental fields. To help attain the expected outcome, the HFA identified five specific priorities for action (PFAs) which are: (i) making disaster risk reduction a priority; (ii) improving risk information and early warning; (iii) building a culture of safety and resilience; (iv) reducing the risks in key sectors; and (v) strengthening preparedness for response. The Global Network of Civil Society Organisation for Disaster Risk Reduction (GNDR) which was launched in 2007 in Geneva, is a major international network of civil society organisations working to influence and implement disaster risk reduction policies and practice around the world. The major programme of the global network is to collect perspective for the local level as to how the HFA is progressing. The Views from the Frontline (VFL) is the first independent assessment project undertaken towards the implementation of the HFA at the local level and is led by the Global Network. The aim of this project is to measure the gap between policy formulation at international level with the realities of policy execution at local level and to deepen the communication and coordination between different stakeholders on disaster risk reduction by involving government organisation and communities at the local level. The VFL perspective is that nationally formulated policies are not generating widespread systematic changes in local practices. There is a concern that the current approach is top–down and engages minimally with affected communities and fails to address their needs and capacities (GNDR, 2008:01). The main objective of this research was to provide an overview of progress made in the implementation of the HFA at local level particularly in the Kabokweni Location. The approach adopted in this study is called 'the Views from the Frontline', and explores the extent of the actual progress made toward the implementation and impact of the HFA priorities at local level, namely the Kabokweni community in the Mbombela Local Municipality (MLM) situated in the Mpumalanga Province of South Africa. / Thesis (M. Development and management)--North-West University, Potchefstroom Campus, 2011.