Inhalation represents a potentially attractive delivery route for biologics, especially those designed to treat pulmonary diseases such as asthma, cystic fibrosis or lung cancer. Delivery directly to the site of action should increase local concentrations of drug, whilst reducing systemic side effects. However, there is limited knowledge regarding the mechanisms of pulmonary clearance, with gaps in understanding; where molecules are absorbed, the mechanisms involved, regional variability throughout the lung, and how to control pulmonary retention and/or facilitate cellular uptake. The work presented in this thesis details the development of a SPECT/CT imaging protocol to determine the pulmonary retention and tissue redistribution of technetium labelled antibodies and their fragments in vivo, in mice, to begin to address these knowledge gaps. The SPECT/CT imaging method was applied to a whole monoclonal murine immunoglobulin G1 (mlgG1), as well as its Fab and scFv fragments and a small protein (FN3) in order to determine whether diffusion controlled pathways were important in pulmonary antibody clearance. Additionally, the pulmonary retention of mutant mlgG1 with differing binding affinities to the murine neonatal Fc receptor (mFcRn) were assessed in order to determine whether antibody transport across the epithelium occurred via active transcytosis. It was determined that 54.4 ± 0.63 % of the total instilled dose of a whole monoclonal antibody remains in the lung over 24 hrs, with Fab and scFv fragments cleared significantly quicker with 28.7 ± 0.73 % and 34.9 ± 0.85 % respectively of the total instilled dose remaining in the lung at 24hrs. The pulmonary retention of the 11 kDa FN3 protein was also assessed with 21.0 ± 0.65 % remaining in the lungs after 24 hrs. No evidence of build up of any protein was detected in the oesophagus/stomach, suggesting little contribution by mucociliary clearance. Very little build up of whole antibody, Fab or scFv was observed in the liver or kidneys. However, very clear evidence of renal filtration of the 11 kDa fragment was observed. There was no difference in the pulmonary retention of wild type IgG and any of the mFcRn binding mutants. Additional investigation of antibody retention rates in the murine house dustmite (HOM) model of asthma, although not making use of the SPECT/CT method, showed that antibody is cleared more rapidly from the diseased lung than the normal lung. It was also shown that the expression pattern of the mFcRn receptor is the same in the normal and HDM exposed lung and so this increase in clearance rate occurs via passive diffusion controlled processes. This is most likely a result of increased paracellular transport due to disrupted mucosal barrier function. The SPECT/CT imaging method developed has proven to be a simple and reliable method to assess, non-invasively, pulmonary antibody retention in vivo. Overall it appears that antibody transport across the pulmonary epithelium occurs predominantly via diffusion controlled mechanisms, which include both paracellular transport and nonspecific transcytosis by pinocytotic routes. Additionally, in the mouse, neither receptor mediated transport by mFcRn nor mucocillary clearance is important in the pulmonary clearance of antibodies.

A multitude of plants have been used extensively for the treatment of cancers throughout the world. In many parts of the world, especially in poor countries, this may be the only form of cancer therapy. Much research has been focused on the scientific evaluation of traditional anti-cancer drugs from the tropical plant; Momordica charantia (MC) is one of them and it has been used frequently as an anti-cancer agent. The green leaves, fruits, seeds and stems of M. charantia composed of many different proteins and steroids that are chemically active. These proteins are α and β momorcharins which possess anti-cancer and anti-HIV properties similar to crude water and methanol soluble extracts of M. charantia. This study investigated the anti cancer effect of either the crude water and methanol soluble extract of M. charantia, α and β and α, β momorcharins based on dose-dependent, time-dependent on the viability of 1321N1, Gos-3, U87-MG, Sk Mel, Corl -23, Weri Rb-1 and L6 cell lines employing different concentrations of each extract or drug. In addition, the study measured the effect of either temozolomide or vinblastine alone or combining each with either the crude water soluble extract of M. charantia or α β momorcharin measuring cell viability in the different cell lines. Furthermore, the present study investigated the cellular mechanism(s) via which the different anti-cancer agents were able to induce cell death measuring the activities of caspase - 3 and caspase - 9, the release of cytochrome c and intracellular free calcium concentrations [Ca 2+ ]i. The results have shown that the crude water soluble extract of M. charantia can evoke both time-course at (800 µg) and dose-dependent (200 µg - 800 µg) decreases in cell viability with maximal increases with 800 µg over a period of 24 hrs following incubation. Either the crude methanol soluble of M. charantia (200 µg - 800 µg), alpha or beta momorcharin (200 µM - 800 µM) had little or no effect on the viability of the different cell lines. In contrast, either alpha, beta momorcharin (200 µM - 800 µM), temozolomide (80 µM - 320 µM) or vinblastine (10 μg - 40 μg) can evoke significant (p < 0.05) decrease in cell viability, similar to the crude water soluble extract of M. charantia. The results also show that combining either temozolomide (240 µM) or vinblastine (40 μg) with either (800 µg) of the crude water- soluble extract of M. charantia or (800 µM) of alpha, beta momorcharin can result in significant decreases in cell viability for each cell line but these effects were neither additive or synergetic compared to the individual effect of temozolomide or vinblastine. The result of this study have also shown that either the crude water-soluble extract of M. charantia (800 µg) or (800 µM) of alpha, beta momorcharin can elicit marked and significant (p < 0.050) increases in the activities of caspase - 3 and caspase - 9 in all the cell lines. Similarly, both the crude water soluble extract of M. charantia and alpha, beta momorcharin can stimulate the release of cytochrome-c and elevated [Ca2+ ]i in the different cancer cell lines compared to untreated cell lines. Together, the results of the study have shown that either the crude water soluble extract of M. charantia or alpha, beta momorcharin can exert their anti-cancer effects (cell death) on cancer cell lines by increasing the activities of caspase - 3 and caspase - 9 and by releasing cytochrome-c and elevating [Ca2+ ]i in the cancer cells. These findings implicate the role of apoptosis and cellular Ca 2+ homeostasis in cancer cell death. Moreover, they confirm the beneficial use of extracts of M. charantia to treat cancers.

Natural products are an important source for drug discovery. At present there is a resurgent interest in pharmacognosy as a platform for new combinations of active principles to provide highly potent and low-cost medications to treat a growing population with an increasing longevity. This product studied phytochemical interactions in Artemisia annua plant extracts using anti-plasmodium and anti-proliferation assays to identify interactions with potential therapeutic implications. To enable the study a rapid tandem quadrupole mass spectrometry (TQD) method was developed for metabolites in the plant and the validation indices showed the method to be robust, quick, sensitive and adequate for a range of applications.

The aim of this study was to evaluate seven GCC regulatory authorities and pharmaceutical companies active in the region in order to identify the strengths and weakness of the current GCC centralised procedure. The GCC regulatory authorities and the pharmaceutical companies who had registered their products through the GCC centralized registration procedure and the national registration systems were recruited into the study and asked to complete the questionnaires specifically designed for this study. The regulatory review process in Oman was evaluated to identify areas for improvement in the system. Information on the total application numbers and approval dates were obtained directly from the Oman Ministry of Health archives. Another study was conducted to evaluate the regulatory review process and approval times of the remaining six GCC countries (Bahrain, Kuwait, Qatar, Saudi Arabia, UAE and Yemen) and the GCC central registration, with respect to review time for new and existing substances, to identify the strengths and weaknesses of the process and to propose strategies that could help the policy maker in the GCC to enhance the review process. The results of the Omani regulatory system showed no significant increase (p>0.05) in the total number of registered pharmaceutical products from 2006 to 2010. The approval time in Oman showed that there was a significant increase in approval times for pharmaceutical products from 2006 to 2010 (p<0.001). The findings show that although there was an increase in the approval time for all pharmaceutical company products, the median approval time for the five year period was 117 days. This was within the time limit (4 months) fixed by the health authority for the overall registration time. The comparative study of the GCC States showed a downward trend in the median approval time for most of the GCC States, during 2008 to 2010. However, the approval time for all approved products in the GCC States during this period varied from 60 days in Qatar and Oman (2009 and 2010) to 609 days in Saudi Arabia (2008). The main reasons for the decrease in approval time in the Gulf States were due to the positive effect of the Gulf Central Registration, the rise in the number of reviewers in some GCC drug authorities, and the parallel procedure used in the regulatory approval review process. The study of the regulatory review process of the GCC central registration showed that a total of 413 products (96 NASs and 317 EASs) were approved during the period 2006-2010 with an overall significant increase in the EASs (p<0.001). The approval times increased from 107 calendar days in 2006 to 265 in 2010 (p<0.001). The lowest approval time was for EASs submitted by the Gulf companies (134 days) and the longest for NASs submitted by international companies (346 days) (p<0.001). VI Both the regulatory authorities and the pharmaceutical companies agreed that the centralised procedure is an effective system for authorising medicinal products in all seven GCC countries in one procedure and is the way forward in the future but there is room for improvement in the procedure and the follow ups. They also agreed that clear guidelines, transparency of procedures, effective interactions between authorities and companies, increase in the number of the committee meetings per year, use of electronic on-line submissions will improve approval time for registration of new medicines, enhance the quality of review practice and encourage the pharmaceutical companies to use the GCC central registration system. This research has enabled development of a new model of the GCC central registration procedure to be proposed for the GCC Health Authorities which could improve patient access to medicines in the GCC states.

This study aimed to evaluate the antimicrobial efficacy of medicinal hemp plant extracts to determine the antibacterial effects of indigenous Sansevieria species and exotic Cannabis sativa phytotherapy varieties. This study also assessed whether aqueous o

<p>Since Helichrysum is known by the indigenous people of Africa for therapeutic properties, such as against colds, flu and wounds, the aim of this study was to focus on the patulum species found predominantly in the Western Cape region of South Africa and by means of isolation and identification of the plant constituents, be able to relate the therapeutic activity on the basis of literature precedents, to the compounds extracted.</p>

<p>Leonotis leonorus and Mentha longifolia are two herbs commonly used in South Africa, mostly in oral liquid dosage forms. Several disadvantages are associated with these traditional dosage forms which can perhaps be remedied by using an appropriate oral solid dosage form, provided the actual plant material in the latter still resemble, as closely as possible, the traditionally used material and provide products of suitable pharmaceutical quality. The objectives of this study were to prepare and evaluate the pharmaceutical suitability of the freeze-dried aqueous extracts of Leonotis Leonorus and Mentha Longifolia as plant raw material for the capsule dosage of these two therapies and to formulate and manufacture capsules of Leonotis Leonorus and Mentha Longifolia aqueous extract that would contain amounts of the plant materials equivalent to that found in their traditional liquid dosage forms, and have immediate release characteristics and suitability stability.</p>

The work in this thesis had two main aims. The first aim was to study the use of a number of precipitation methods to control the size and morphology of precursor phosphor materials for potential applications in a new generation of high definition and field emission displays. The morphological and luminescent characteristics of these precursor phosphor materials were studied after they were annealed to form their respective luminescent oxides using electron microscopy and light measuring techniques. The first set of experiments presented describes the development of a range of spherical submicron europium-doped yttrium oxide phosphor particles and their optimisation for use in the aforementioned applications. A homogeneous precipitation technique exploiting a hydrothermal decomposition of urea that provides hydroxycarbonate phosphor precursor ligands is at the centre of this work. In the presence of rare earth element nitrates the hydroxycarbonate ligands form spherical phosphor precursor particles that after annealing yield the luminescent oxides. This is followed by the presentation of a novel synthetic method using a micellar phase of rare earth element chlorides, after annealing, yielding europium-doped yttrium oxide. This method produces a variety of morphologies with crystallites as small as a few nanometres and up to hundreds of nanometres. Next is described a new precipitation method using ammonia and carbon dioxide gases that are introduced in a controlled manner into a solution of rare earth element chlorides at room temperature. Rare earth element hydroxycarbonates rapidly precipitate upon supersaturation, yielding a range of morphologies and particles sizes. The second aim of the thesis was to prepare a novel range of three-dimensional photonic band gap materials composed of conventional phosphor materials.

The public international backlash against the TRIPS Agreement and the global pharmaceutical industry that followed in the wake of the March 2001 lawsuit brought by 39 pharmaceutical companies against the government of South Africa prompted a critical investigation into how the current order came into being and how it might be in a process of changing. To do this the thesis follows Cox’s insight in Critical IPE that each successive historical structure generates the contradictions and points of conflict that bring about its transformation (Cox, 1995: 35). The research therefore first looks at the making of the patent provisions in TRIPS as a case study in institutional capture by the transnational drug industry (TDI), dominated by American interests. This question is developed theoretically as well as empirically by first developing a theoretical framework that explains continuity in the global political economy (GPE) as a way of intimating how the TDI was able to secure all of its demands for pharmaceutical patents under TRIPS despite the prevalence of conflict and opposition from developing countries in the Uruguay Round (UR), and notwithstanding the single undertaking of the UR package. The thesis then examines the negotiations on patents in the UR to determine the nature of decision-making and to probe the questions of conflict and contradictions in the present that provide a framework of analysis on the shakiness of the prevailing order. The thesis then looks at how, why and under what circumstances the initial ‘capture’ of TRIPS by the TDI was arguably successfully challenged by probably the weakest global economic actor, the African Group (AG) at the WTO. Specifically looking at the role of conflict in change this question probes further points of conflict and contradictions in the present to set the scene for the wide scale offensive against TRIPS as a result of its implications for access to healthcare in the poorest countries which already suffer overwhelmingly from a high disease burden. The post-TRIPS challenge mounted by transnational civil society and the AG (the two constituting a counter-society) take the thesis from its analysis of continuity in the GPE, towards theorising the circumstances under which the prevailing historical structure can at least partially be transcended to render legitimate the demands of the poor. The thesis advances its contribution, both theoretically and empirically, to Critical International Political Economy, particularly as it concerns the work of Robert Cox.

In recent years the pharmaceutical industry has seen a rise in the number of drug compounds with low aqueous solubility, and consequently poor oral bioavailablility. One potential solution to this problem is to formulate such compounds as solid dispersions, whereby the drug is dispersed in a carrier matrix in the solid state. In this thesis, the hypothesis that a number of drug-drug and drug-polymer intermolecular interactions influence the physical stability and dissolution performance of solid dispersions is considered. The aim is to use correlations between drug molecular structure and solid dispersion performance to develop a platform to rapidly assess whether drug compounds will have favourable properties when formulated as a solid dispersion. Amorphous felodipine/copovidone solid dispersions are used as a model system to develop a suitable testing regime with regards to physical stability and dissolution performance. A laser light scattering technique developed in this work shows that morphological changes in felodipine/copovidone films exposed to water are due to polymer swelling. A combination of dissolution testing methodologies is also used to suggest a mechanism for the dissolution of bulk solid dispersion samples. Contributions of individual functional groups in the felodipine analogues to the physical stability and dissolution performance of their amorphous solid dispersions are assessed. Blocking of the felodipine amine hydrogen-bond-donor with an N-methyl, and the removal of chlorine substituents are both shown to reduce the physical stability of the solid dispersions. Correlations between molecular descriptors and data from the above experiments show that drug compounds are more likely to crystallise from solid dispersions with copovidone if they have a low log P, low relative molecular mass and low polarizability. Such correlations can form the basis of a screening method for the molecular design of analogous drug compounds likely to form high-performance solid dispersions with copovidone.